Therapeutic combinations of a BTK inhibitor, a PI3K inhibitor and/or a JAK-2 inhibitor

ABSTRACT

Therapeutic combinations of a Janus kinase-2 (JAK-2) inhibitor, a Bruton&#39;s tyrosine kinase (BTK) inhibitor, and/or a phosphoinositide 3-kinase (PI3K) inhibitor, including PI3K inhibitors selective for the γ- and δ-isoforms and selective for both γ- and δ-isoforms, are described. In some embodiments, the invention provides pharmaceutical compositions comprising combinations of (1) a PI3K-δ inhibitor and a BTK inhibitor, (2) a JAK-2 inhibitor and a BTK inhibitor, or (3) a JAK-2 inhibitor, PI3K-δ inhibitor, and BTK inhibitor, and methods of using the pharmaceutical compositions for treating a disease, in particular a cancer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/013,506 filed on Jun. 17, 2014; U.S. Provisional Application No.62/035,785 filed on Aug. 11, 2014; U.S. Provisional Application No.62/087,975 filed on Dec. 5, 2014; and U.S. Provisional Application No.62/115,493 filed on Feb. 12, 2015, all of which are herein incorporatedby reference in their entireties.

SEQUENCE LISTING

Sequence Listing Submission via EFS-Web. A computer readable text file,entitled “SequenceListing.txt,” created on or about 16 Dec. 2016 with afile size of about 14 kb contains the sequence listing for thisapplication and is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

Therapeutic combinations of a phosphoinositide 3-kinase (PI3K)inhibitor, a Janus kinase-2 (JAK-2) inhibitor, and a Bruton's tyrosinekinase (BTK) inhibitor and uses of the therapeutic combinations aredisclosed herein. In particular, a combination of a BTK inhibitor and aJAK-2 inhibitor and uses thereof are disclosed.

BACKGROUND OF THE INVENTION

PI3K kinases are members of a unique and conserved family ofintracellular lipid kinases that phosphorylate the 3′-OH group onphosphatidylinositols or phosphoinositides. PI3K kinases are keysignaling enzymes that relay signals from cell surface receptors todownstream effectors. The PI3K family comprises 15 kinases with distinctsubstrate specificities, expression patterns, and modes of regulation.The class I PI3K kinases (p110α, p110β, p110δ, and p110γ) are typicallyactivated by tyrosine kinases or G-protein coupled receptors to generatePIP3, which engages downstream effectors such as those in the Akt/PDK1pathway, mTOR, the Tec family kinases, and the Rho family GTPases.

The PI3K signaling pathway is known to be one of the most highly mutatedin human cancers. PI3K signaling is also a key factor in disease statesincluding hematologic malignancies, non-Hodgkin lymphoma (such asdiffuse large B-cell lymphoma), allergic contact dermatitis, rheumatoidarthritis, osteoarthritis, inflammatory bowel diseases, chronicobstructive pulmonary disorder, psoriasis, multiple sclerosis, asthma,disorders related to diabetic complications, and inflammatorycomplications of the cardiovascular system such as acute coronarysyndrome. The role of PI3K in cancer has been discussed, for example, inJ. A. Engleman, Nat. Rev. Cancer 2009, 9, 550-562. The PI3K-δ and PI3K-γisoforms are preferentially expressed in normal and malignantleukocytes.

The delta (6) isoform of class I PI3K (PI3K-δ) is involved in mammalianimmune system functions such as T-cell function, B-cell activation, mastcell activation, dendritic cell function, and neutrophil activity. Dueto its role in immune system function, PI3K-δ is also involved in anumber of diseases related to undesirable immune response such asallergic reactions, inflammatory diseases, inflammation mediatedangiogenesis, rheumatoid arthritis, auto-immune diseases such as lupus,asthma, emphysema and other respiratory diseases. The gamma (γ) isoformof class I PI3K (PI3K-γ) is also involved in immune system functions andplays a role in leukocyte signaling and has been implicated ininflammation, rheumatoid arthritis, and autoimmune diseases such aslupus.

Downstream mediators of the PI3K signal transduction pathway include Aktand mammalian target of rapamycin (mTOR). One important function of Aktis to augment the activity of mTOR, through phosphorylation of TSC2 andother mechanisms. mTOR is a serine-threonine kinase related to the lipidkinases of the PI3K family and has been implicated in a wide range ofbiological processes including cell growth, cell proliferation, cellmotility and survival. Disregulation of the mTOR pathway has beenreported in various types of cancer.

In view of the above, PI3K inhibitors are prime targets for drugdevelopment, as described in J. E. Kurt and I. Ray-Coquard, AnticancerRes. 2012, 32, 2463-70. Several PI3K inhibitors are known, includingthose that are PI3K-δ or PI3K-γ inhibitors and those that are PI3K-δ,γinhibitors.

Bruton's Tyrosine Kinase (BTK) is a Tec family non-receptor proteinkinase expressed in B cells and myeloid cells. The function of BTK insignaling pathways activated by the engagement of the B cell receptor(BCR) and FCER1 on mast cells is well established. Functional mutationsin BTK in humans result in a primary immunodeficiency diseasecharacterized by a defect in B cell development with a block betweenpro- and pre-B cell stages. The result is an almost complete absence ofB lymphocytes, causing a pronounced reduction of serum immunoglobulin ofall classes. These findings support a key role for BTK in the regulationof the production of auto-antibodies in autoimmune diseases.

Other diseases with an important role for dysfunctional B cells are Bcell malignancies. The reported role for BTK in the regulation ofproliferation and apoptosis of B cells indicates the potential for BTKinhibitors in the treatment of B cell lymphomas. BTK inhibitors havethus been developed as potential therapies, as described in O. J. D'Cruzand F. M. Uckun, OncoTargets and Therapy 2013, 6, 161-176.

Janus kinase-2 (JAK-2) is an enzyme that is a member of the Janus kinasefamily of four cytoplasmic tyrosine kinases that also includes JAK-1,JAK-3, and Tyk2 (tyrosine kinase 2). The Janus kinase family transducescytokine-mediated signals as part of the JAK-STAT signalling pathway(where STAT is an acronym for “signal transducer and activator oftranscription”), as described in K. Ghoreschi, A. Laurence, J. J.O'Shea, Janus kinases in immune cell signaling. Immunol. Rev. 2009, 228,273-287. The JAK-STAT pathway mediates signalling by cytokines thataffects proliferation, differentiation, and survival in many cell types,and is commonly expressed in leukocytes. The Janus kinase family ofenzymes is required for signaling by cytokine and growth factorreceptors that lack intrinsic kinase activity. JAK-2 is implicated insignaling processes by members of the type II cytokine receptor family(such as interferon receptors), the GM-CSF receptor family (IL-3R, IL-5Rand GM-CSF-R), the gpl30 receptor family (e.g. IL-6R), and the singlechain receptors (e.g. Epo-R, Tpo-R, GH-R, PRL-R), as described in U.S.Patent Application Publication No. 2012/0157500, the disclosure of whichis incorporated herein by reference. JAK-2 signaling is activateddownstream from the prolactin receptor. JAK-2 inhibitors were developedafter discovery of an activating tyrosine kinase mutation (the V617Fmutation) in myeloproliferative cancers and disorders. JAK-2 inhibitorshave been developed as potential therapies for myeloproliferativeneoplasms, polycythemia vera, essential thrombocythemia, and primarymyelofibrosis, as discussed in S. Verstovsek, Therapeutic potential ofJAK2 inhibitors, Hematology (American Society of Hematology EducationBook), 2009, 636-642. JAK-2 inhibitorsmay reverse hyperphosphorylationof JAK-2 and effectively treat myeloproliferative cancers and disorders.

In many solid tumors, the supportive microenvironment (which may make upthe majority of the tumor mass) is a dynamic force that enables tumorsurvival. The tumor microenvironment is generally defined as a complexmixture of “cells, soluble factors, signaling molecules, extracellularmatrices, and mechanical cues that promote neoplastic transformation,support tumor growth and invasion, protect the tumor from host immunity,foster therapeutic resistance, and provide niches for dominantmetastases to thrive,” as described in Swartz, et al., Cancer Res.,2012, 72, 2473. Although tumors express antigens that should berecognized by T cells, tumor clearance by the immune system is rarebecause of immune suppression by the microenvironment. Addressing thetumor cells themselves with e.g. chemotherapy has also proven to beinsufficient to overcome the protective effects of the microenvironment.New approaches are thus urgently needed for more effective treatment ofsolid tumors that take into account the role of the microenvironment.

The CD20 antigen, also called human B-lymphocyte-restricteddifferentiation antigen Bp35, or B1), is found on the surface of normal“pre-B” and mature B lymphocytes, including malignant B lymphocytes.Nadler, et al., J. Clin. Invest. 1981, 67, 134-40; Stashenko, et al., J.Immunol. 1980, 139, 3260-85. The CD20 antigen is a glycosylated integralmembrane protein with a molecular weight of approximately 35 kD. Tedder,et al., Proc. Natl. Acad. Sci. USA, 1988, 85, 208-12. CD20 is alsoexpressed on most B cell non-Hodgkin's lymphoma cells, but is not foundon hematopoietic stem cells, pro-B cells, normal plasma cells, or othernormal tissues. Anti-CD20 antibodies are currently used as therapies formany B cell hematological malignancies, including indolent non-Hodgkin'slymphoma (NHL), aggressive NHL, and chronic lymphocytic leukemia(CLL)/small lymphocytic leukemia (SLL). Lim, et. al., Haematologica2010, 95, 135-43; Beers, et. al., Sem. Hematol. 2010, 47, 107-14; Klein,et al., mAbs 2013, 5, 22-33. However, there is an urgent need to providefor more efficiacious therapies in many B cell hematologicalmalignancies.

The present invention provides the unexpected finding that thecombination of a JAK-2 inhibitor and a BTK inhibitor is synergisticallyeffective in the treatment of any of several types of cancers such asleukemia, lymphoma, and solid tumor cancers. The present invention alsoprovides the unexpected finding that a combination of a PI3K inhibitor,a JAK-2 inhibitor, and a BTK inhibitor is synergistically effective inthe treatment of any of several types of cancers such as leukemia,lymphoma, and solid tumor cancers. The present invention furtherprovides the unexpected finding that the combination of a JAK-2inhibitor and a PI3K inhibitor is synergistically effective in thetreatment of any of several types of cancers such as leukemia, lymphoma,and solid tumor cancers. The present invention further provides theunexpected finding that the combination of a PI3K inhibitor and a BTKinhibitor is synergistically effective in the treatment of any ofseveral types of cancers such as leukemia, lymphoma, and solid tumorcancers. The present invention further provides the unexpected findingthat the combination of an anti-CD20 antibody with a BTK inhibitor, aPI3K inhibitor, and/or a JAK-2 inhibitor, is synergistically effectivein the treatment of any of several types of cancers such as leukemia,lymphoma, and solid tumor cancers.

SUMMARY OF THE INVENTION

In an embodiment, the invention provides a method of treating ahyperproliferative disease, comprising co-administering, to a mammal inneed thereof, therapeutically effective amounts of (1) a Janus kinase-2(JAK-2) inhibitor or a pharmaceutically acceptable salt, solvate,hydrate, cocrystal, or prodrug thereof, and (2) a Bruton's tyrosinekinase (BTK) inhibitor or a pharmaceutically acceptable salt, solvate,hydrate, cocrystal, or prodrug thereof. In an embodiment, the JAK-2inhibitor is administered to the mammal before administration of the BTKinhibitor. In an embodiment, the JAK-2 inhibitor is administered to themammal simultaneously with the administration of the BTK inhibitor. Inan embodiment, the JAK-2 inhibitor is administered to the mammal afteradministration of the BTK inhibitor.

In an embodiment, the invention provides a method of treating ahyperproliferative disease, comprising co-administering, to a mammal inneed thereof, therapeutically effective amounts of (1) a Janus kinase-2(JAK-2) inhibitor or a pharmaceutically acceptable salt, solvate,hydrate, cocrystal, or prodrug thereof, and (2) a Bruton's tyrosinekinase (BTK) inhibitor or a pharmaceutically acceptable salt, solvate,hydrate, cocrystal, or prodrug thereof, wherein the BTK inhibitor isselected from the group consisting of:

and pharmaceutically-acceptable salts, cocrystals, hydrates, solvates,and prodrugs thereof.

In an embodiment, the invention provides a method of treating ahyperproliferative disease, comprising co-administering, to a mammal inneed thereof, therapeutically effective amounts of (1) a Janus kinase-2(JAK-2) inhibitor or a pharmaceutically acceptable salt, solvate,hydrate, cocrystal, or prodrug thereof, and (2) a Bruton's tyrosinekinase (BTK) inhibitor or a pharmaceutically acceptable salt, solvate,hydrate, cocrystal, or prodrug thereof, wherein the BTK inhibitor isselected from the group consisting of:

and pharmaceutically-acceptable salts, cocrystals, hydrates, solvates,and prodrugs thereof.

In an embodiment, the invention provides a method of treating ahyperproliferative disease, comprising co-administering, to a mammal inneed thereof, therapeutically effective amounts of (1) a Janus kinase-2(JAK-2) inhibitor or a pharmaceutically acceptable salt, solvate,hydrate, cocrystal, or prodrug thereof, and (2) a Bruton's tyrosinekinase (BTK) inhibitor or a pharmaceutically acceptable salt, solvate,hydrate, cocrystal, or prodrug thereof, wherein the JAK-2 inhibitor isselected from the group consisting of:

and pharmaceutically-acceptable salts, cocrystals, hydrates, solvates,or prodrugs thereof.

In an embodiment, the invention provides a method of treating ahyperproliferative disease, comprising co-administering, to a mammal inneed thereof, therapeutically effective amounts of (1) a Janus kinase-2(JAK-2) inhibitor or a pharmaceutically acceptable salt, solvate,hydrate, cocrystal, or prodrug thereof, and (2) a Bruton's tyrosinekinase (BTK) inhibitor or a pharmaceutically acceptable salt, solvate,hydrate, cocrystal, or prodrug thereof, further comprising the step ofadministering a therapeutically effective amount of an anti-CD20antibody selected from the group consisting of rituximab, obinutuzumab,ofatumumab, veltuzumab, tositumomab, ibritumomab, and fragments,derivatives, conjugates, variants, radioisotope-labeled complexes,biosimilars thereof, and combinations thereof.

In an embodiment, the invention provides a method of treating ahyperproliferative disease, comprising co-administering, to a mammal inneed thereof, therapeutically effective amounts of (1) a Janus kinase-2(JAK-2) inhibitor or a pharmaceutically acceptable salt, solvate,hydrate, cocrystal, or prodrug thereof, and (2) a Bruton's tyrosinekinase (BTK) inhibitor or a pharmaceutically acceptable salt, solvate,hydrate, cocrystal, or prodrug thereof, further comprising the step ofadministering a phosphoinositide 3-kinase (PI3K) inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. In an embodiment, the PI3K inhibitor is a PI3K-δinhibitor. In an embodiment, the PI3K inhibitor is administered to themammal before administration of the BTK inhibitor. In an embodiment,wherein the PI3K inhibitor is administered to the mammal concurrentlywith the administration of the BTK inhibitor. In an embodiment, the PI3Kinhibitor is administered to the mammal after administration of the BTKinhibitor. In an embodiment, the PI3K inhibitor is selected from thegroup consisting of:

and pharmaceutically acceptable salts, solvates, hydrates, cocrystals,and prodrugs thereof.

In an embodiment, the invention provides a method of treating ahyperproliferative disease, wherein the hyperproliferative disease is acancer, comprising co-administering, to a mammal in need thereof,therapeutically effective amounts of (1) a Janus kinase-2 (JAK-2)inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof, and (2) a Bruton's tyrosine kinase (BTK)inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof, wherein the cancer is a B cellhematological malignancy, and wherein the B cell hematologicalmalignancy is selected from the group consisting of chronic lymphocyticleukemia (CLL), small lymphocytic leukemia (SLL), non-Hodgkin's lymphoma(NHL), diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL),mantle cell lymphoma (MCL), Hodgkin's lymphoma, B cell acutelymphoblastic leukemia (B-ALL), Burkitt's lymphoma, Waldenström'smacroglobulinemia (WM), Burkitt's lymphoma, multiple myeloma, andmyelofibrosis. In an embodiment, the cancer is a solid tumor cancer,wherein the solid tumor cancer is selected from the group consisting ofbladder cancer, non-small cell lung cancer, cervical cancer, analcancer, pancreatic cancer, squamous cell carcinoma including head andneck cancer, renal cell carcinoma, melanoma, ovarian cancer, small celllung cancer, glioblastoma, gastrointestinal stromal tumor, breastcancer, lung cancer, colorectal cancer, thyroid cancer, bone sarcoma,stomach cancer, oral cavity cancer, oropharyngeal cancer, gastriccancer, kidney cancer, liver cancer, prostate cancer, esophageal cancer,testicular cancer, gynecological cancer, colon cancer, and brain cancer.

In an embodiment, the invention provides a method of treating ahyperproliferative disease, comprising co-administering, to a mammal inneed thereof, therapeutically effective amounts of (1) a Janus kinase-2(JAK-2) inhibitor or a pharmaceutically acceptable salt, solvate,hydrate, cocrystal, or prodrug thereof, and (2) a Bruton's tyrosinekinase (BTK) inhibitor or a pharmaceutically acceptable salt, solvate,hydrate, cocrystal, or prodrug thereof, further comprising the step ofadministering a therapeutically effective amount of gemcitabine oralbumin-bound paclitaxel.

In an embodiment, the invention provides a method of treating a cancerin a human comprising the step of co-administering (1) a therapeuticallyeffective amount of a Janus kinase-2 (JAK-2) inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, and (2) a therapeutically effective amount of aBruton's tyrosine kinase (BTK) inhibitor or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof,wherein the therapeutically effective amount is effective to inhibitsignaling between the tumor cells of the cancer and at least one tumormicroenvironment selected from the group consisting of macrophages,monocytes, mast cells, helper T cells, cytotoxic T cells, regulatory Tcells, natural killer cells, myeloid-derived suppressor cells,regulatory B cells, neutrophils, dendritic cells, and fibroblasts. In anembodiment, the cancer is a solid tumor cancer selected from the groupconsisting of bladder cancer, non-small cell lung cancer, cervicalcancer, anal cancer, pancreatic cancer, squamous cell carcinomaincluding head and neck cancer, renal cell carcinoma, melanoma, ovariancancer, small cell lung cancer, glioblastoma, gastrointestinal stromaltumor, breast cancer, lung cancer, colorectal cancer, thyroid cancer,bone sarcoma, stomach cancer, oral cavity cancer, oropharyngeal cancer,gastric cancer, kidney cancer, liver cancer, prostate cancer, esophagealcancer, testicular cancer, gynecological cancer, colon cancer, and braincancer. In an embodiment, the BTK inhibitor is selected from the groupconsisting of:

and pharmaceutically-acceptable salts, cocrystals, hydrates, solvates,or prodrugs thereof. In an embodiment, the JAK-2 inhibitor is selectedfrom the group consisting of:

and pharmaceutically-acceptable salts, cocrystals, hydrates, solvates,and prodrugs thereof.

In an embodiment, the invention provides a method of treating a cancerin a human intolerant to a bleeding event comprising the step ofadministering (1) a therapeutically effective amount of a Janus kinase-2(JAK-2) inhibitor or a pharmaceutically acceptable salt, solvate,hydrate, cocrystal, or prodrug thereof, and (2) a therapeuticallyeffective amount of a Bruton's tyrosine kinase (BTK) inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, wherein the BTK inhibitor is selected from the groupconsisting of:

and pharmaceutically-acceptable salts, cocrystals, hydrates, solvates,or prodrugs thereof. In an embodiment, the bleeding event is selectedfrom the group consisting of subdural hematoma, gastrointestinalbleeding, hematuria, post-procedural hemorrhage, bruising, petechiae,and combinations thereof. In an embodiment, the JAK-2 inhibitor isselected from the group consisting of:

and pharmaceutically-acceptable salts, cocrystals, hydrates, solvates,and prodrugs thereof.

In an embodiment, the invention provides a method of treating a cancerin a human intolerant to a bleeding event comprising the step ofadministering (1) a therapeutically effective amount of a Janus kinase-2(JAK-2) inhibitor or a pharmaceutically acceptable salt, solvate,hydrate, cocrystal, or prodrug thereof, and (2) a therapeuticallyeffective amount of a Bruton's tyrosine kinase (BTK) inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, further comprising the step of administering atherapeutically effective amount of an anticoagulant or antiplateletactive pharmaceutical ingredient. In an embodiment, the anticoagulant orantiplatelet active pharmaceutical ingredient is selected from the groupconsisting of acenocoumarol, anagrelide, anagrelide hydrochloride,abciximab, aloxiprin, antithrombin, apixaban, argatroban, aspirin,aspirin with extended-release dipyridamole, beraprost, betrixaban,bivalirudin, carbasalate calcium, cilostazol, clopidogrel, clopidogrelbisulfate, cloricromen, dabigatran etexilate, darexaban, dalteparin,dalteparin sodium, defibrotide, dicumarol, diphenadione, dipyridamole,ditazole, desirudin, edoxaban, enoxaparin, enoxaparin sodium,eptifibatide, fondaparinux, fondaparinux sodium, heparin, heparinsodium, heparin calcium, idraparinux, idraparinux sodium, iloprost,indobufen, lepirudin, low molecular weight heparin, melagatran,nadroparin, otamixaban, parnaparin, phenindione, phenprocoumon,prasugrel, picotamide, prostacyclin, ramatroban, reviparin, rivaroxaban,sulodexide, terutroban, terutroban sodium, ticagrelor, ticlopidine,ticlopidine hydrochloride, tinzaparin, tinzaparin sodium, tirofiban,tirofiban hydrochloride, treprostinil, treprostinil sodium, triflusal,vorapaxar, warfarin, warfarin sodium, ximelagatran, salts thereof,solvates thereof, hydrates thereof, and combinations thereof. In anembodiment, the cancer is selected from the group consisting of bladdercancer, squamous cell carcinoma including head and neck cancer,pancreatic ductal adenocarcinoma (PDA), pancreatic cancer, coloncarcinoma, mammary carcinoma, breast cancer, fibrosarcoma, mesothelioma,renal cell carcinoma, lung carcinoma, thyoma, prostate cancer,colorectal cancer, ovarian cancer, acute myeloid leukemia, thymuscancer, brain cancer, squamous cell cancer, skin cancer, eye cancer,retinoblastoma, melanoma, intraocular melanoma, oral cavity andoropharyngeal cancers, gastric cancer, stomach cancer, cervical cancer,renal cancer, kidney cancer, liver cancer, ovarian cancer, esophagealcancer, testicular cancer, gynecological cancer, thyroid cancer, aquiredimmune deficiency syndrome (AIDS)-related cancers (e.g., lymphoma andKaposi's sarcoma), viral-induced cancer, glioblastoma, esophogealtumors, hematological neoplasms, non-small-cell lung cancer, chronicmyelocytic leukemia, diffuse large B-cell lymphoma, esophagus tumor,follicle center lymphoma, head and neck tumor, hepatitis C virusinfection, hepatocellular carcinoma, Hodgkin's disease, metastatic coloncancer, multiple myeloma, non-Hodgkin's lymphoma, indolent non-Hogkin'slymphoma, ovary tumor, pancreas tumor, renal cell carcinoma, small-celllung cancer, stage IV melanoma, chronic lymphocytic leukemia, B-cellacute lymphoblastic leukemia (ALL), mature B-cell ALL, follicularlymphoma, mantle cell lymphoma, Burkitt's lymphoma, and myelofibrosis.

In some embodiments, the invention provides a composition comprisingtherapeutically effective amounts of (1) a JAK-2 inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; and (2) a BTK inhibitor or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, foruse in the treatment of cancer. This composition is typically apharmaceutical composition.

In some embodiments, the invention provides a composition comprisingtherapeutically effective amounts of (1) a JAK-2 inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; (2) a BTK inhibitor or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof; and (3) a PI3Kinhibitor or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof. This composition is typically apharmaceutical composition.

In some embodiments, the invention provides a composition comprisingtherapeutically effective amounts of (1) a JAK-2 inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; (2) a BTK inhibitor or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof; and (3) a PI3K-δinhibitor or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof. This composition is typically apharmaceutical composition.

In some embodiments, the invention provides a composition comprisingtherapeutically effective amounts of (1) a JAK-2 inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; (2) a BTK inhibitor or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof; and (3) a PI3K-γinhibitor or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof. This composition is typically apharmaceutical composition.

In some embodiments, the invention provides a composition comprisingtherapeutically effective amounts of (1) a JAK-2 inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; (2) a BTK inhibitor or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof; and (3) aPI3K-γ,δ inhibitor or a pharmaceutically acceptable salt, solvate,hydrate, cocrystal, or prodrug thereof. This composition is typically apharmaceutical composition.

In some embodiments, the invention provides a composition comprisingtherapeutically effective amounts of (1) a JAK-2 inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; (2) a BTK inhibitor or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof, for use in thetreatment of cancer; and (3) a therapeutically effective amount of ananti-CD20 antibody selected from the group consisting of rituximab,obinutuzumab, ofatumumab, veltuzumab, tositumomab, ibritumomab, andfragments, derivatives, conjugates, variants, radioisotope-labeledcomplexes, and biosimilars thereof. This composition is typically apharmaceutical composition.

In some embodiments, the invention provides a composition comprisingtherapeutically effective amounts of (1) a JAK-2 inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; (2) a BTK inhibitor or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof; (3) a PI3Kinhibitor or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof; and (4) a therapeutically effectiveamount of an anti-CD20 antibody selected from the group consisting ofrituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab,ibritumomab, and fragments, derivatives, conjugates, variants,radioisotope-labeled complexes, and biosimilars thereof. Thiscomposition is typically a pharmaceutical composition.

In some embodiments, the invention provides a method of treatingleukemia, lymphoma or a solid tumor cancer in a subject, comprisingco-administering to a mammal in need thereof any of the foregoingcompositions.

In some embodiments, the invention provides a method of treatingleukemia, lymphoma or a solid tumor cancer in a subject, comprisingco-administering to a mammal in need thereof a therapeutically effectiveamount of a PI3K inhibitor and a BTK inhibitor.

In some embodiments, the invention provides a method of treatingleukemia, lymphoma or a solid tumor cancer in a subject, comprisingco-administering to a mammal in need thereof a therapeutically effectiveamount of a PI3K-γ inhibitor and a BTK inhibitor.

In some embodiments, the invention provides a method of treatingleukemia, lymphoma or a solid tumor cancer in a subject, comprisingco-administering to a mammal in need thereof a therapeutically effectiveamount of a PI3K-δ inhibitor and a BTK inhibitor.

In some embodiments, the invention provides a method of treatingleukemia, lymphoma or a solid tumor cancer in a subject, comprisingco-administering to a mammal in need thereof a therapeutically effectiveamount of a PI3K-γ,δ inhibitor and a BTK inhibitor.

In some embodiments, the invention provides a method of treatingleukemia, lymphoma or a solid tumor cancer in a subject, comprisingco-administering to a mammal in need thereof a therapeutically effectiveamount of a JAK-2 inhibitor and a BTK inhibitor.

In some embodiments, the invention provides a method of treatingleukemia, lymphoma or a solid tumor cancer in a subject, comprisingco-administering to a mammal in need thereof a therapeutically effectiveamount of a PI3K inhibitor, a JAK-2 inhibitor, and a BTK inhibitor.

In some embodiments, the invention provides a method of treatingleukemia, lymphoma or a solid tumor cancer in a subject, comprisingco-administering to a mammal in need thereof a therapeutically effectiveamount of a PI3K-γ inhibitor, a JAK-2 inhibitor, and a BTK inhibitor.

In some embodiments, the invention provides a method of treatingleukemia, lymphoma or a solid tumor cancer in a subject, comprisingco-administering to a mammal in need thereof a therapeutically effectiveamount of a PI3K-δ inhibitor, a JAK-2 inhibitor, and a BTK inhibitor.

In some embodiments, the invention provides a method of treatingleukemia, lymphoma or a solid tumor cancer in a subject, comprisingco-administering to a mammal in need thereof a therapeutically effectiveamount of a PI3K-γ,δ inhibitor, a JAK-2 inhibitor, and a BTK inhibitor.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing summary, as well as the following detailed description ofthe invention, will be better understood when read in conjunction withthe appended drawings.

FIG. 1 illustrates the sensitivity of the TMD8 diffuse large B celllymphoma (DLBCL) cell line to individual treatment with the BTKinhibitor of Formula (XVIII) (“Tested Btk Inhibitor”) and the PI3Kinhibitor of Formula (IX) (“Tested PI3K Inhibitor”) and combinedtreatment with Formula (XVIII) and Formula (IX) (“Btki+PI3Ki”) atdifferent concentrations. The concentration of the first activepharmaceutical ingredient in the combination (the BTK inhibitor) and theconcentration of the individual active pharmaceutical ingredients isgiven on the x-axis, and the concentration of the added PI3K inhibitorin combination with the BTK inhibitor is given in the legend.

FIG. 2 illustrates the sensitivity of the MINO mantle cell lymphoma cellto individual treatment with the BTK inhibitor of Formula (XVIII)(“Tested Btk Inhibitor”) and the PI3K inhibitor of Formula (IX) (“TestedPI3K Inhibitor”) and combined treatment with Formula (XVIII) and Formula(IX) (“Btki+PI3Ki”) at different concentrations. The concentration ofthe first active pharmaceutical ingredient in the combination (the BTKinhibitor) and the concentration of the individual active pharmaceuticalingredients is given on the x-axis, and the concentration of the addedPI3K inhibitor in combination with the BTK inhibitor is given in thelegend.

FIG. 3 illustrates the activity in primary mantle cell lymphoma cells ofFormula (XVIII) (“Tested Btki”) and Formula (IX) (“Tested PI3Ki”). Thepercentage viability of cells (“% viability”, y-axis) is plotted versusthe concentration of the active pharmaceutical ingredient(s). Treatmentwith single BTK (“Tested Btki”) or PI3K inhibitors (“Tested PI3Ki”) iscompared to four combinations of Formula (XVIII) and Formula (IX) (“(10μM) Tested PI3Ki”, “(1.0 μM) Tested PI3Ki,” “(0.1 μM) Tested PI3Ki,”“(0.01 μM) Tested PI3Ki”).

FIG. 4 illustrates the interaction index of the combination of the BTKinhibitor of Formula (XVIII) and the PI3K inhibitor of Formula (IX) inprimary mantle cell lymphoma cells from different patients (MCL-1 toMCL-5). Each symbol represents a concentration from 10 μM to 0.1 nM.

FIG. 5 illustrates the synergy observed in certain cell lines when theBTK inhibitor of Formula (XVIII) and the PI3K-δ inhibitor of Formula(IX) are combined. The tested cell lines include Maver-1 (B celllymphoma, mantle), Jeko (B cell lymphoma, mantle), CCRF (B lymphoblast,acute lymphoblastic leukemia), and SUP-B15 (B lymphoblast, acutelymphoblastic leukemia). The dose-effect curves for these cell lines aregiven in FIG. 6, FIG. 7, FIG. 8, and FIG. 9. ED25, ED50, ED75, and ED90refer to the effective doses causing 25%, 50%, 75%, and 90% of themaximum biological effect (proliferation).

FIG. 6 illustrates the dose-effect curves obtained for the testedMaver-1 cell line (B cell lymphoma, mantle) using combined dosing of theBTK inhibitor of Formula (XVIII) (“Inh.1”) and the PI3K-δ inhibitor ofFormula (IX) (“Inh.3”). The y-axis (“Effect”) is given in units of Fa(fraction affected) and the x-axis (“Dose”) is given in linear units ofμM.

FIG. 7 illustrates the dose-effect curves obtained for the tested Jekocell line (B cell lymphoma, mantle) using combined dosing of the BTKinhibitor of Formula (XVIII) (“Inh.1”) and the PI3K-δ inhibitor ofFormula (IX) (“Inh.3”). The y-axis (“Effect”) is given in units of Fa(fraction affected) and the x-axis (“Dose”) is given in linear units ofμM.

FIG. 8 illustrates the dose-effect curves obtained for the tested CCRFcell line (B lymphoblast, acute lymphoblastic leukemia) using combineddosing of the BTK inhibitor of Formula (XVIII) (“Inh.1”) and the PI3K-δinhibitor of Formula (IX) (“Inh.3”). The y-axis (“Effect”) is given inunits of Fa (fraction affected) and the x-axis (“Dose”) is given inlinear units of μM.

FIG. 9 illustrates the dose-effect curves obtained for the testedSUP-B15 cell line (B lymphoblast, acute lymphoblastic leukemia) usingcombined dosing of the BTK inhibitor of Formula (XVIII) (“Inh.1”) andthe PI3K-δ inhibitor of Formula (IX) (“Inh.3”). The y-axis (“Effect”) isgiven in units of Fa (fraction affected) and the x-axis (“Dose”) isgiven in linear units of μM.

FIG. 10 illustrates the synergy observed in certain cell lines when theBTK inhibitor of Formula (XVIII) and the PI3K-δ inhibitor of Formula(IX) are combined. The tested cell lines include Jeko (B cell lymphoma,mantle cell lymphoma) and SU-DHL-4 (activated B cell like (ABC) diffuselarge B cell lymphoma). The dose-effect curves for these cell lines aregiven in FIG. 11 and FIG. 12.

FIG. 11 illustrates the dose-effect curves obtained for the tested Jekocell line (B cell lymphoma, mantle) using combined dosing of the BTKinhibitor of Formula (XVIII) (“Inh.1”) and the PI3K-δ inhibitor ofFormula (IX) (“Inh.3”). The y-axis (“Effect”) is given in units of Fa(fraction affected) and the x-axis (“Dose”) is given in linear units ofμM.

FIG. 12 illustrates the dose-effect curves obtained for the testedSU-DHL-4 cell line (diffuse large B cell lymphoma, ABC) using combineddosing of the BTK inhibitor of Formula (XVIII) (“Inh.1”) and the PI3K-δinhibitor of Formula (IX) (“Inh.3”). The y-axis (“Effect”) is given inunits of Fa (fraction affected) and the x-axis (“Dose”) is given inlinear units of μM.

FIG. 13 illustrates the synergy observed in certain cell lines when theBTK inhibitor of Formula (XVIII) and the PI3K-δ inhibitor of Formula(IX) are combined. The tested cell lines include CCRF (B lymphoblast,acute lymphoblastic leukemia), SUP-B15 (B lymphoblast, acutelymphoblastic leukemia), JVM-2 (prolymphocytic leukemia), Ramos(Burkitt's lymphoma), and Mino (mantle cell lymphoma). The dose-effectcurves for these cell lines are given in FIG. 14, FIG. 15, FIG. 16, andFIG. 17. No dose-effect curve is given for Ramos (Burkitt's lymphoma)because of negative slope.

FIG. 14 illustrates the dose-effect curves obtained for the tested CCRFcell line (B lymphoblast, acute lymphoblastic leukemia) using combineddosing of the BTK inhibitor of Formula (XVIII) (“Inh.1”) and the PI3K-δinhibitor of Formula (IX) (“Inh.3”). The y-axis (“Effect”) is given inunits of Fa (fraction affected) and the x-axis (“Dose”) is given inlinear units of μM.

FIG. 15 illustrates the dose-effect curves obtained for the testedSUP-B15 cell line (B lymphoblast, acute lymphoblastic leukemia) usingcombined dosing of the BTK inhibitor of Formula (XVIII) (“Inh.1”) andthe PI3K-δ inhibitor of Formula (IX) (“Inh.3”). The y-axis (“Effect”) isgiven in units of Fa (fraction affected) and the x-axis (“Dose”) isgiven in linear units of μM.

FIG. 16 illustrates the dose-effect curves obtained for the tested JVM-2cell line (prolymphocytic leukemia) using combined dosing of the BTKinhibitor of Formula (XVIII) (“Inh.1”) and the PI3K-δ inhibitor ofFormula (IX) (“Inh.3”). The y-axis (“Effect”) is given in units of Fa(fraction affected) and the x-axis (“Dose”) is given in linear units ofμM.

FIG. 17 illustrates the dose-effect curves obtained for the tested Minocell line (mantle cell lymphoma) using combined dosing of the BTKinhibitor of Formula (XVIII) (“Inh.1”) and the PI3K-δ inhibitor ofFormula (IX) (“Inh.3”). The y-axis (“Effect”) is given in units of Fa(fraction affected) and the x-axis (“Dose”) is given in linear units ofμM.

FIG. 18 illustrates the synergy observed in certain cell lines when theBTK inhibitor of Formula (XVIII) and the PI3K-δ inhibitor of Formula(IX) are combined. The tested cell lines include Raji (B lymphocyte,Burkitt's lymphoma), SU-DHL-1 (DLBCL-ABC), and Pfeiffer (follicularlymphoma). The dose-effect curves for these cell lines are given in FIG.19, FIG. 20, and FIG. 21.

FIG. 19 illustrates the dose-effect curves obtained for the tested Rajicell line (B lymphocyte, Burkitt's lymphoma) using combined dosing ofthe BTK inhibitor of Formula (XVIII) (“Inh.1”) and the PI3K-δ inhibitorof Formula (IX) (“Inh.3”). The y-axis (“Effect”) is given in units of Fa(fraction affected) and the x-axis (“Dose”) is given in linear units ofμM.

FIG. 20 illustrates the dose-effect curves obtained for the testedSU-DHL-1 cell line (DLBCL-ABC) using combined dosing of the BTKinhibitor of Formula (XVIII) (“Inh.1”) and the PI3K-δ inhibitor ofFormula (IX) (“Inh.3”). The y-axis (“Effect”) is given in units of Fa(fraction affected) and the x-axis (“Dose”) is given in linear units ofμM.

FIG. 21 illustrates the dose-effect curves obtained for the testedPfeiffer cell line (follicular lymphoma) using combined dosing of theBTK inhibitor of Formula (XVIII) (“Inh.1”) and the PI3K-δ inhibitor ofFormula (IX) (“Inh.3”). The y-axis (“Effect”) is given in units of Fa(fraction affected) and the x-axis (“Dose”) is given in linear units ofμM.

FIG. 22 illustrates the synergy observed in certain cell lines when theBTK inhibitor of Formula (XVIII) and the PI3K-δ inhibitor of Formula(IX) are combined. The tested cell lines include Ly1 (Germinal centerB-cell like diffuse large B-cell lymphoma, DLBCL-GCB), Ly7 (DLBCL-GCB),Ly19 (DLBCL-GCB), SU-DHL-2 (Activated B-cell like diffuse large B-celllymphoma, DLBCL-ABC), and DOHH2 (follicular lymophoma, FL). Thedose-effect curves for these cell lines are given in FIG. 23, FIG. 24,FIG. 25, and FIG. 26, except for the Ly19 cell line, which is notgraphed because of a negative slope.

FIG. 23 illustrates the dose-effect curves obtained for the tested Ly1cell line (DLBCL-GCB) using combined dosing of the BTK inhibitor ofFormula (XVIII) (“Inh.1”) and the PI3K-δ inhibitor of Formula (IX)(“Inh.3”). The y-axis (“Effect”) is given in units of Fa (fractionaffected) and the x-axis (“Dose”) is given in linear units of μM.

FIG. 24 illustrates the dose-effect curves obtained for the tested Ly7cell line (DLBCL-GCB) using combined dosing of the BTK inhibitor ofFormula (XVIII) (“Inh.1”) and the PI3K-δ inhibitor of Formula (IX)(“Inh.3”). The y-axis (“Effect”) is given in units of Fa (fractionaffected) and the x-axis (“Dose”) is given in linear units of μM.

FIG. 25 illustrates the dose-effect curves obtained for the tested DOHH2cell line (FL) using combined dosing of the BTK inhibitor of Formula(XVIII) (“Inh.1”) and the PI3K-δ inhibitor of Formula (IX) (“Inh.3”).The y-axis (“Effect”) is given in units of Fa (fraction affected) andthe x-axis (“Dose”) is given in linear units of μM.

FIG. 26 illustrates the dose-effect curves obtained for the testedSU-DHL-2 cell line (DLBCL-ABC) using combined dosing of the BTKinhibitor of Formula (XVIII) (“Inh.1”) and the PI3K-δ inhibitor ofFormula (IX) (“Inh.3”). The y-axis (“Effect”) is given in units of Fa(fraction affected) and the x-axis (“Dose”) is given in linear units ofμM.

FIG. 27 illustrates the synergy observed in certain cell lines whenFormula (XVIII) and Formula (IX) are combined. The tested cell linesinclude U937 (histiocytic lymphoma and/or myeloid), K562 (leukemia,myeloid, and/or chronic myelogenous leukemia), Daudi (human Burkitt'slymphoma), and SU-DHL-6 (DLBCL-GCB and/or peripheral T-cell lymphoma,PTCL). The dose-effect curves for these cell lines are given in FIG. 28,FIG. 29, FIG. 30, and FIG. 31.

FIG. 28 illustrates the dose-effect curves obtained for the tested U937cell line (histiocytic lymphoma and/or myeloid) using combined dosing ofthe BTK inhibitor of Formula (XVIII) (“Inh.1”) and the PI3K-δ inhibitorof Formula (IX) (“Inh.3”). The y-axis (“Effect”) is given in units of Fa(fraction affected) and the x-axis (“Dose”) is given in linear units ofμM.

FIG. 29 illustrates the dose-effect curves obtained for the tested K562cell line (leukemia, myeloid, and/or chronic myelogenous leukemia) usingcombined dosing of the BTK inhibitor of Formula (XVIII) (“Inh.1”) andthe PI3K-δ inhibitor of Formula (IX) (“Inh.3”). The y-axis (“Effect”) isgiven in units of Fa (fraction affected) and the x-axis (“Dose”) isgiven in linear units of μM.

FIG. 30 illustrates the dose-effect curves obtained for the tested Daudicell line (human Burkitt's lymphoma) using combined dosing of the BTKinhibitor of Formula (XVIII) (“Inh.1”) and the PI3K-δ inhibitor ofFormula (IX) (“Inh.3”). The y-axis (“Effect”) is given in units of Fa(fraction affected) and the x-axis (“Dose”) is given in linear units ofμM.

FIG. 31 illustrates the dose-effect curves obtained for the testedSU-DHL-6 cell line (DLBCL-GCB and/or PTCL) using combined dosing of theBTK inhibitor of Formula (XVIII) (“Inh.1”) and the PI3K-δ inhibitor ofFormula (IX) (“Inh.3”). The y-axis (“Effect”) is given in units of Fa(fraction affected) and the x-axis (“Dose”) is given in linear units ofμM.

FIG. 32 illustrates the synergy observed in certain cell lines when theBTK inhibitor of Formula (XVIII) and the PI3K-δ inhibitor of Formula(IX) are combined. The tested cell lines include SU-DHL-6 (DLBCL-GCB orPTCL), TMD-8 (DLBCL-ABC), HBL-1 (DLBCL-ABC), and Rec-1 (follicularlymphoma). The dose-effect curves for these cell lines are given in FIG.34, FIG. 35, FIG. 36, and FIG. 37.

FIG. 33 illustrates the synergy observed in certain cell lines when theBTK inhibitor of Formula (XVIII) and the PI3K-δ inhibitor of Formula(IX) are combined. The tested cell lines include SU-DHL-6 (DLBCL-GCB orPTCL), TMD-8 (DLBCL-ABC), HBL-1 (DLBCL-ABC), and Rec-1 (follicularlymphoma). All corresponding CIs are shown for each of the combinationstested as listed on the x axis.

FIG. 34 illustrates the dose-effect curves obtained for the testedSU-DHL-6 cell line (DLBCL-GCB or PTCL) cell line using combined dosingof the BTK inhibitor of Formula (XVIII) (“Inh.1”) and the PI3K-δinhibitor of Formula (IX) (“Inh.3”). The y-axis (“Effect”) is given inunits of Fa (fraction affected) and the x-axis (“Dose”) is given inlinear units of μM.

FIG. 35 illustrates the dose-effect curves obtained for the tested TMD-8cell line (DLBCL-ABC) using combined dosing of the BTK inhibitor ofFormula (XVIII) (“Inh.1”) and the PI3K-δ inhibitor of Formula (IX)(“Inh.3”). The y-axis (“Effect”) is given in units of Fa (fractionaffected) and the x-axis (“Dose”) is given in linear units of μM.

FIG. 36 illustrates the dose-effect curves obtained for the tested HBL-1cell line (DLBCL-ABC) using combined dosing of the BTK inhibitor ofFormula (XVIII) (“Inh.”) and the PI3K-δ inhibitor of Formula (IX)(“Inh.3”). The y-axis (“Effect”) is given in units of Fa (fractionaffected) and the x-axis (“Dose”) is given in linear units of μM.

FIG. 37 illustrates the dose-effect curves obtained for the tested Rec-1cell line (follicular lymphoma) using combined dosing of the BTKinhibitor of Formula (XVIII) (“Inh.1”) and the PI3K-δ inhibitor ofFormula (IX) (“Inh.3”). The y-axis (“Effect”) is given in units of Fa(fraction affected) and the x-axis (“Dose”) is given in linear units ofμM.

FIG. 38 illustrates the synergy observed in certain cell lines when theBTK inhibitor of Formula (XVIII) and the JAK-2 inhibitor of Formula XXX(ruxolitinib) are combined. The tested cell lines included Maver-1 (Bcell lymphoma, mantle), Jeko (B cell lymphoma, mantle), SUP-B15 (Blymphoblast, acute lymphoblastic leukemia), and CCRF (B lymphoblast,acute lymphoblastic leukemia). The dose-effect curves for these celllines are given in FIG. 39, FIG. 40, FIG. 41, and FIG. 42.

FIG. 39 illustrates the dose-effect curves obtained for the testedMaver-1 cell line (B cell lymphoma, mantle) using combined dosing of theBTK inhibitor of Formula (XVIII) (“Inh.1”) and the JAK-2 inhibitor ofFormula XXX (“Inh.2”) (ruxolitinib). The y-axis (“Effect”) is given inunits of Fa (fraction affected) and the x-axis (“Dose”) is given inlinear units of μM.

FIG. 40 illustrates the dose-effect curves obtained for the tested Jekocell line (B cell lymphoma, mantle) using combined dosing of the BTKinhibitor of Formula (XVIII) (“Inh.1”) and the JAK-2 inhibitor ofFormula XXX (“Inh.2”) (ruxolitinib). The y-axis (“Effect”) is given inunits of Fa (fraction affected) and the x-axis (“Dose”) is given inlinear units of μM.

FIG. 41 illustrates the dose-effect curves obtained for the testedSUP-B15 cell line (B lymphoblast, acute lymphoblastic leukemia) usingcombined dosing of the BTK inhibitor of Formula (XVIII) (“Inh.1”) andthe JAK-2 inhibitor of Formula XXX (“Inh.2”) (ruxolitinib). The y-axis(“Effect”) is given in units of Fa (fraction affected) and the x-axis(“Dose”) is given in linear units of μM.

FIG. 42 illustrates the dose-effect curves obtained for the tested CCRFcell line (B lymphoblast, acute lymphoblastic leukemia) using combineddosing of the BTK inhibitor of Formula (XVIII) (“Inh.1”) and the JAK-2inhibitor of Formula XXX (“Inh.2”) (ruxolitinib). The y-axis (“Effect”)is given in units of Fa (fraction affected) and the x-axis (“Dose”) isgiven in linear units of μM.

FIG. 43 illustrates the synergy observed in certain cell lines when theBTK inhibitor of Formula (XVIII) and the JAK-2 inhibitor of Formula XXX(ruxolitinib) are combined. Repeat experiments for two of the cell linespreviously shown in FIG. 38 are shown, including SUP-B15 (B lymphoblast,acute lymphoblastic leukemia) and CCRF (B lymphoblast, acutelymphoblastic leukemia).

FIG. 44 illustrates the synergy observed in certain cell lines when theBTK inhibitor of Formula (XVIII) and the JAK-2 inhibitor of Formula XXX(ruxolitinib) are combined. The tested cell lines included JVM-2(prolymphocytic leukemia), Raji (B lymphocyte, Burkitt's lymphoma),Ramos (B lymphocyte, Burkitt's lymphoma), and Mino (mantle celllymphoma). The dose-effect curves for these cell lines are given in FIG.45, FIG. 46, FIG. 47, and FIG. 48.

FIG. 45 illustrates the dose-effect curves obtained for the tested JVM-2cell line (prolymphocytic leukemia) using combined dosing of the BTKinhibitor of Formula (XVIII) (“Inh.1”) and the JAK-2 inhibitor ofFormula XXX (“Inh.2”) (ruxolitinib). The y-axis (“Effect”) is given inunits of Fa (fraction affected) and the x-axis (“Dose”) is given inlinear units of μM.

FIG. 46 illustrates the dose-effect curves obtained for the tested Rajicell line (B lymphocyte, Burkitt's lymphoma) using combined dosing ofthe BTK inhibitor of Formula (XVIII) (“Inh.1”) and the JAK-2 inhibitorof Formula XXX (“Inh.2”) (ruxolitinib). The y-axis (“Effect”) is givenin units of Fa (fraction affected) and the x-axis (“Dose”) is given inlinear units of μM.

FIG. 47 illustrates the dose-effect curves obtained for the tested Ramoscell line (B lymphocyte, Burkitt's lymphoma) using combined dosing ofthe BTK inhibitor of Formula (XVIII) (“Inh.1”) and the JAK-2 inhibitorof Formula XXX (“Inh.2”) (ruxolitinib). The y-axis (“Effect”) is givenin units of Fa (fraction affected) and the x-axis (“Dose”) is given inlinear units of μM.

FIG. 48 illustrates the dose-effect curves obtained for the tested Minocell line (mantle cell lymphoma) using combined dosing of the BTKinhibitor of Formula (XVIII) (“Inh.1”) and the JAK-2 inhibitor ofFormula XXX (“Inh.2”) (ruxolitinib). The y-axis (“Effect”) is given inunits of Fa (fraction affected) and the x-axis (“Dose”) is given inlinear units of μM.

FIG. 49 illustrates the synergy observed in certain cell lines when theBTK inhibitor of Formula (XVIII) and the JAK-2 inhibitor of Formula XXX(ruxolitinib) are combined. The tested cell lines included Pfeiffer(follicular lymphoma) and SU-DHL-1 (DLBCL-ABC). The dose-effect curvesfor these cell lines are given in FIG. 50 and FIG. 51.

FIG. 50 illustrates the dose-effect curves obtained for the testedPfeiffer cell line (follicular lymphoma) using combined dosing of theBTK inhibitor of Formula (XVIII) (“Inh.1”) and the JAK-2 inhibitor ofFormula XXX (“Inh.2”) (ruxolitinib). The y-axis (“Effect”) is given inunits of Fa (fraction affected) and the x-axis (“Dose”) is given inlinear units of μM.

FIG. 51 illustrates the dose-effect curves obtained for the testedSU-DHL-1 cell line (follicular lymphoma) using combined dosing of theBTK inhibitor of Formula (XVIII) (“Inh.1”) and the JAK-2 inhibitor ofFormula XXX (“Inh.2”) (ruxolitinib). The y-axis (“Effect”) is given inunits of Fa (fraction affected) and the x-axis (“Dose”) is given inlinear units of μM.

FIG. 52 illustrates the synergy observed in certain cell lines when theBTK inhibitor of Formula (XVIII) and the JAK-2 inhibitor of Formula XXX(ruxolitinib) are combined. The tested cell lines included DOHH2(follicular lymphoma), SU-DHL-1 (DLBCL-ABC), Ly1 (DLBCL-GCB), Ly7(DLBCL-GCB), and Ly19 (DLBCL-GCB). The dose-effect curves for these celllines are given in FIG. 53, FIG. 54, FIG. 55, and FIG. 56, except forthe Ly19 cell line, which is not graphed because of a negative slope.

FIG. 53 illustrates the dose-effect curves obtained for the tested DOHH2cell line (follicular lymphoma) using combined dosing of the BTKinhibitor of Formula (XVIII) (“Inh.1”) and the JAK-2 inhibitor ofFormula XXX (“Inh.2”) (ruxolitinib). The y-axis (“Effect”) is given inunits of Fa (fraction affected) and the x-axis (“Dose”) is given inlinear units of μM.

FIG. 54 illustrates the dose-effect curves obtained for the testedSU-DHL-1 cell line (DLBCL-ABC) using combined dosing of the BTKinhibitor of Formula (XVIII) (“Inh.1”) and the JAK-2 inhibitor ofFormula XXX (“Inh.2”) (ruxolitinib). The y-axis (“Effect”) is given inunits of Fa (fraction affected) and the x-axis (“Dose”) is given inlinear units of μM.

FIG. 55 illustrates the dose-effect curves obtained for the tested Ly1cell line (DLBCL-GCB) using combined dosing of the BTK inhibitor ofFormula (XVIII) (“Inh.1”) and the JAK-2 inhibitor of Formula XXX(“Inh.2”) (ruxolitinib). The y-axis (“Effect”) is given in units of Fa(fraction affected) and the x-axis (“Dose”) is given in linear units ofμM.

FIG. 56 illustrates the dose-effect curves obtained for the tested Ly7cell line (DLBCL-GCB) using combined dosing of the BTK inhibitor ofFormula (XVIII) (“Inh.1”) and the JAK-2 inhibitor of Formula XXX(“Inh.2”) (ruxolitinib). The y-axis (“Effect”) is given in units of Fa(fraction affected) and the x-axis (“Dose”) is given in linear units ofμM.

FIG. 57 illustrates the synergy observed in certain cell lines when theBTK inhibitor of Formula (XVIII) and the JAK-2 inhibitor of Formula XXX(ruxolitinib) are combined. The tested cell lines included U937(histiocytic lymphoma), Daudi (human Burkitt's lymphoma), and K562(leukemia, myeloid, and/or chronic myelogenous leukemia). Thedose-effect curves for these cell lines are given in FIG. 58, FIG. 59,and FIG. 60.

FIG. 58 illustrates the dose-effect curves obtained for the tested U937cell line (histiocytic lymphoma) using combined dosing of the BTKinhibitor of Formula (XVIII) (“Inh.1”) and the JAK-2 inhibitor ofFormula XXX (“Inh.2”) (ruxolitinib). The y-axis (“Effect”) is given inunits of Fa (fraction affected) and the x-axis (“Dose”) is given inlinear units of μM.

FIG. 59 illustrates the dose-effect curves obtained for the tested Daudicell line (human Burkitt's lymphoma) using combined dosing of the BTKinhibitor of Formula (XVIII) (“Inh.1”) and the JAK-2 inhibitor ofFormula XXX (“Inh.2”) (ruxolitinib). The y-axis (“Effect”) is given inunits of Fa (fraction affected) and the x-axis (“Dose”) is given inlinear units of μM.

FIG. 60 illustrates the dose-effect curves obtained for the tested K562cell line (leukemia, myeloid, and/or chronic myelogenous leukemia) usingcombined dosing of the BTK inhibitor of Formula (XVIII) (“Inh.1”) andthe JAK-2 inhibitor of Formula XXX (“Inh.2”) (ruxolitinib). The y-axis(“Effect”) is given in units of Fa (fraction affected) and the x-axis(“Dose”) is given in linear units of μM.

FIG. 61 illustrates the synergy observed in certain cell lines when theBTK inhibitor of Formula (XVIII) and the JAK-2 inhibitor of Formula XXX(ruxolitinib) are combined. The tested cell lines include SU-DHL-6(DLBCL-GCB or PTCL), TMD-8 (DLBCL-ABC), HBL-1 (DLBCL-ABC), and Rec-1(follicular lymphoma). The dose-effect curves for these cell lines aregiven in FIG. 62, FIG. 63, FIG. 64, and FIG. 65.

FIG. 62 illustrates the dose-effect curves obtained for the testedSU-DHL-6 cell line (DLBCL-GCB or PTCL) using combined dosing of the BTKinhibitor of Formula (XVIII) (“Inh.1”) and the JAK-2 inhibitor ofFormula XXX (“Inh.2”) (ruxolitinib). The y-axis (“Effect”) is given inunits of Fa (fraction affected) and the x-axis (“Dose”) is given inlinear units of μM.

FIG. 63 illustrates the dose-effect curves obtained for the tested TMD-8cell line (DLBCL-ABC) using combined dosing of the BTK inhibitor ofFormula (XVIII) (“Inh.1”) and the JAK-2 inhibitor of Formula XXX(“Inh.2”) (ruxolitinib). The y-axis (“Effect”) is given in units of Fa(fraction affected) and the x-axis (“Dose”) is given in linear units ofPIM.

FIG. 64 illustrates the dose-effect curves obtained for the tested HBL-1cell line (DLBCL-ABC) using combined dosing of the BTK inhibitor ofFormula (XVIII) (“Inh.1”) and the JAK-2 inhibitor of Formula XXX(“Inh.2”) (ruxolitinib). The y-axis (“Effect”) is given in units of Fa(fraction affected) and the x-axis (“Dose”) is given in linear units ofμM.

FIG. 65 illustrates the dose-effect curves obtained for the tested Rec-1cell line (follicular lymphoma) using combined dosing of the BTKinhibitor of Formula (XVIII) (“Inh.1”) and the JAK-2 inhibitor ofFormula XXX (“Inh.2”) (ruxolitinib). The y-axis (“Effect”) is given inunits of Fa (fraction affected) and the x-axis (“Dose”) is given inlinear units of μM.

FIG. 66 illustrates the synergy observed in certain cell lines when theBTK inhibitor of Formula (XVIII) and the JAK-2 inhibitor of Formula LIV(pacritinib) are combined. The tested cell lines include Mino (mantlecell lymphoma), Maver-1 (B cell lymphoma, mantle cell lymophoma), Raji(B lymphocyte, Burkitt's lymphoma), JVM-2 (prolymphocytic leukemia),Daudi (Human Burkitt's lymphoma), Rec-1 (follicular lymphoma), SUP-B15(B lymphoblast, acute lymphoblastic leukemia), CCRF (B lymphoblast,acute lymphoblastic leukemia), and SU-DHL-4 (DLBCL-ABC). The dose-effectcurves for these cell lines are given in FIG. 67, FIG. 68, FIG. 69, FIG.70, FIG. 71, FIG. 72, FIG. 73, FIG. 74, and FIG. 75.

FIG. 67 illustrates the dose-effect curves obtained for the tested Minocell line (mantle cell lymphoma) using combined dosing of the BTKinhibitor of Formula (XVIII) (“Inh.1”) and the JAK-2 inhibitor ofFormula LIV (“Inh.4”) (pacritinib). The y-axis (“Effect”) is given inunits of Fa (fraction affected) and the x-axis (“Dose”) is given inlinear units of μM.

FIG. 68 illustrates the dose-effect curves obtained for the testedMaver-1 cell line (B cell lymphoma, mantle cell lymophoma) usingcombined dosing of the BTK inhibitor of Formula (XVIII) (“Inh.1”) andthe JAK-2 inhibitor of Formula LIV (“Inh.4”) (pacritinib). The y-axis(“Effect”) is given in units of Fa (fraction affected) and the x-axis(“Dose”) is given in linear units of μM.

FIG. 69 illustrates the dose-effect curves obtained for the tested Rajicell line (B lymphocyte, Burkitt's lymphoma) using combined dosing ofthe BTK inhibitor of Formula (XVIII) (“Inh.1”) and the JAK-2 inhibitorof Formula LIV (“Inh.4”) (pacritinib). The y-axis (“Effect”) is given inunits of Fa (fraction affected) and the x-axis (“Dose”) is given inlinear units of μM.

FIG. 70 illustrates the dose-effect curves obtained for the tested JVM-2cell line (prolymphocytic leukemia) using combined dosing of the BTKinhibitor of Formula (XVIII) (“Inh.1”) and the JAK-2 inhibitor ofFormula LIV (“Inh.4”) (pacritinib). The y-axis (“Effect”) is given inunits of Fa (fraction affected) and the x-axis (“Dose”) is given inlinear units of μM.

FIG. 71 illustrates the dose-effect curves obtained for the tested Daudicell line (Human Burkitt's lymphoma) using combined dosing of the BTKinhibitor of Formula (XVIII) (“Inh.1”) and the JAK-2 inhibitor ofFormula LIV (“Inh.4”) (pacritinib). The y-axis (“Effect”) is given inunits of Fa (fraction affected) and the x-axis (“Dose”) is given inlinear units of μM.

FIG. 72 illustrates the dose-effect curves obtained for the tested Rec-1cell line (follicular lymphoma) using combined dosing of the BTKinhibitor of Formula (XVIII) (“Inh.1”) and the JAK-2 inhibitor ofFormula LIV (“Inh.4”) (pacritinib). The y-axis (“Effect”) is given inunits of Fa (fraction affected) and the x-axis (“Dose”) is given inlinear units of μM.

FIG. 73 illustrates the dose-effect curves obtained for the testedSUP-B15 cell line (B lymphoblast, acute lymphoblastic leukemia) usingcombined dosing of the BTK inhibitor of Formula (XVIII) (“Inh.1”) andthe JAK-2 inhibitor of Formula LIV (“Inh.4”) (pacritinib). The y-axis(“Effect”) is given in units of Fa (fraction affected) and the x-axis(“Dose”) is given in linear units of μM.

FIG. 74 illustrates the dose-effect curves obtained for the tested CCRFcell line (B lymphoblast, acute lymphoblastic leukemia) using combineddosing of the BTK inhibitor of Formula (XVIII) (“Inh.1”) and the JAK-2inhibitor of Formula LIV (“Inh.4”) (pacritinib). The y-axis (“Effect”)is given in units of Fa (fraction affected) and the x-axis (“Dose”) isgiven in linear units of μM.

FIG. 75 illustrates the dose-effect curves obtained for the testedSU-DHL-4 cell line (DLBCL-ABC) using combined dosing of the BTKinhibitor of Formula (XVIII) (“Inh.1”) and the JAK-2 inhibitor ofFormula LIV (“Inh.4”) (pacritinib). The y-axis (“Effect”) is given inunits of Fa (fraction affected) and the x-axis (“Dose”) is given inlinear units of μM.

FIG. 76 illustrates the synergy observed in certain cell lines when theBTK inhibitor of Formula (XVIII) and the JAK-2 inhibitor of Formula LIV(pacritinib) are combined. The tested cell lines include EB3 (Blymphocyte, Burkitt's lymphoma), CA46 (B lymphocyte, Burkitt'slymphoma), DB (B cell lymphoma, mantle cell lymphoma), Pfeiffer(follicular lymphoma), DOHH2 (follicular lymphoma), Namalwa (Blymphocyte, Burkitt's lymphoma), JVM-13 (B cell lymphoma, mantle celllymphoma), SU-DHL-1 (DLBCL-ABC), and SU-DHL-2 (DLBCL-ABC). Thedose-effect curves for these cell lines are given in FIG. 77, FIG. 78,FIG. 79, FIG. 80, FIG. 81, FIG. 82, FIG. 83, FIG. 84, and FIG. 85.

FIG. 77 illustrates the dose-effect curves obtained for the tested EB3cell line (B lymphocyte, Burkitt's lymphoma) using combined dosing ofthe BTK inhibitor of Formula (XVIII) (“Inh.1”) and the JAK-2 inhibitorof Formula LIV (“Inh.4”) (pacritinib). The y-axis (“Effect”) is given inunits of Fa (fraction affected) and the x-axis (“Dose”) is given inlinear units of μM.

FIG. 78 illustrates the dose-effect curves obtained for the tested CA46cell line (B lymphocyte, Burkitt's lymphoma) using combined dosing ofthe BTK inhibitor of Formula (XVIII) (“Inh.1”) and the JAK-2 inhibitorof Formula LIV (“Inh.4”) (pacritinib). The y-axis (“Effect”) is given inunits of Fa (fraction affected) and the x-axis (“Dose”) is given inlinear units of μM.

FIG. 79 illustrates the dose-effect curves obtained for the tested DBcell line (B cell lymphoma, mantle cell lymphoma) using combined dosingof the BTK inhibitor of Formula (XVIII) (“Inh.1”) and the JAK-2inhibitor of Formula LIV (“Inh.4”) (pacritinib). The y-axis (“Effect”)is given in units of Fa (fraction affected) and the x-axis (“Dose”) isgiven in linear units of μM.

FIG. 80 illustrates the dose-effect curves obtained for the testedPfeiffer cell line (follicular lymphoma) using combined dosing of theBTK inhibitor of Formula (XVIII) (“Inh.1”) and the JAK-2 inhibitor ofFormula LIV (“Inh.4”) (pacritinib). The y-axis (“Effect”) is given inunits of Fa (fraction affected) and the x-axis (“Dose”) is given inlinear units of μM.

FIG. 81 illustrates the dose-effect curves obtained for the tested DOHH2cell line (follicular lymphoma) using combined dosing of the BTKinhibitor of Formula (XVIII) (“Inh.1”) and the JAK-2 inhibitor ofFormula LIV (“Inh.4”) (pacritinib). The y-axis (“Effect”) is given inunits of Fa (fraction affected) and the x-axis (“Dose”) is given inlinear units of μM.

FIG. 82 illustrates the dose-effect curves obtained for the testedNamalwa cell line (B lymphocyte, Burkitt's lymphoma) using combineddosing of the BTK inhibitor of Formula (XVIII) (“Inh.1”) and the JAK-2inhibitor of Formula LIV (“Inh.4”) (pacritinib). The y-axis (“Effect”)is given in units of Fa (fraction affected) and the x-axis (“Dose”) isgiven in linear units of μM.

FIG. 83 illustrates the dose-effect curves obtained for the testedJVM-13 cell line (B cell lymphoma, mantle cell lymphoma) using combineddosing of the BTK inhibitor of Formula (XVIII) (“Inh.1”) and the JAK-2inhibitor of Formula LIV (“Inh.4”) (pacritinib). The y-axis (“Effect”)is given in units of Fa (fraction affected) and the x-axis (“Dose”) isgiven in linear units of μM.

FIG. 84 illustrates the dose-effect curves obtained for the testedSU-DHL-1 cell line (DLBCL-ABC) using combined dosing of the BTKinhibitor of Formula (XVIII) (“Inh.1”) and the JAK-2 inhibitor ofFormula LIV (“Inh.4”) (pacritinib). The y-axis (“Effect”) is given inunits of Fa (fraction affected) and the x-axis (“Dose”) is given inlinear units of μM.

FIG. 85 illustrates the dose-effect curves obtained for the testedSU-DHL-2 cell line (DLBCL-ABC) using combined dosing of the BTKinhibitor of Formula (XVIII) (“Inh.1”) and the JAK-2 inhibitor ofFormula LIV (“Inh.4”) (pacritinib). The y-axis (“Effect”) is given inunits of Fa (fraction affected) and the x-axis (“Dose”) is given inlinear units of μM.

FIG. 86 illustrates the synergy observed in certain cell lines when theBTK inhibitor of Formula (XVIII) and the JAK-2 inhibitor of Formula LIV(pacritinib) are combined. The tested cell lines include Jeko (B celllymphoma, mantle cell lymphoma), TMD-8 (DLBCL-ABC), SU-DHL6 (DLBCL-GCB),Ramos (human Burkitt's lymphoma), HBL-1 (DLBCL-ABC), SU-DHL-10(DLBCL-GCB), OCI-Ly7 (DLBCL-ABC), and OCI-Ly3 (DLBCL-ABC). Thedose-effect curves for these cell lines are given in FIG. 87, FIG. 88,FIG. 89, FIG. 90, FIG. 91, FIG. 92, FIG. 93, and FIG. 94.

FIG. 87 illustrates the dose-effect curves obtained for the tested Jekocell line (B cell lymphoma, mantle cell lymphoma) using combined dosingof the BTK inhibitor of Formula (XVIII) (“Inh.1”) and the JAK-2inhibitor of Formula LIV (“Inh.4”) (pacritinib). The y-axis (“Effect”)is given in units of Fa (fraction affected) and the x-axis (“Dose”) isgiven in linear units of μM.

FIG. 88 illustrates the dose-effect curves obtained for the tested TMD-8cell line (DLBCL-ABC) using combined dosing of the BTK inhibitor ofFormula (XVIII) (“Inh.1”) and the JAK-2 inhibitor of Formula LIV(“Inh.4”) (pacritinib). The y-axis (“Effect”) is given in units of Fa(fraction affected) and the x-axis (“Dose”) is given in linear units ofμM.

FIG. 89 illustrates the dose-effect curves obtained for the testedSU-DHL6 cell line (DLBCL-GCB) using combined dosing of the BTK inhibitorof Formula (XVIII) (“Inh.1”) and the JAK-2 inhibitor of Formula LIV(“Inh.4”) (pacritinib). The y-axis (“Effect”) is given in units of Fa(fraction affected) and the x-axis (“Dose”) is given in linear units ofμM.

FIG. 90 illustrates the dose-effect curves obtained for the tested Ramoscell line (human Burkitt's lymphoma) using combined dosing of the BTKinhibitor of Formula (XVIII) (“Inh.1”) and the JAK-2 inhibitor ofFormula LIV (“Inh.4”) (pacritinib). The y-axis (“Effect”) is given inunits of Fa (fraction affected) and the x-axis (“Dose”) is given inlinear units of μM.

FIG. 91 illustrates the dose-effect curves obtained for the tested HBL-1cell line (DLBCL-ABC) using combined dosing of the BTK inhibitor ofFormula (XVIII) (“Inh.1”) and the JAK-2 inhibitor of Formula LIV(“Inh.4”) (pacritinib). The y-axis (“Effect”) is given in units of Fa(fraction affected) and the x-axis (“Dose”) is given in linear units ofμM.

FIG. 92 illustrates the dose-effect curves obtained for the testedSU-DHL-10 cell line (DLBCL-GCB) using combined dosing of the BTKinhibitor of Formula (XVIII) (“Inh.1”) and the JAK-2 inhibitor ofFormula LIV (“Inh.4”) (pacritinib). The y-axis (“Effect”) is given inunits of Fa (fraction affected) and the x-axis (“Dose”) is given inlinear units of μM.

FIG. 93 illustrates the dose-effect curves obtained for the testedOCI-Ly7 cell line (DLBCL-ABC) using combined dosing of the BTK inhibitorof Formula (XVIII) (“Inh.1”) and the JAK-2 inhibitor of Formula LIV(“Inh.4”) (pacritinib). The y-axis (“Effect”) is given in units of Fa(fraction affected) and the x-axis (“Dose”) is given in linear units ofμM.

FIG. 94 illustrates the dose-effect curves obtained for the testedOCI-Ly3 cell line (DLBCL-ABC) using combined dosing of the BTK inhibitorof Formula (XVIII) (“Inh.1”) and the JAK-2 inhibitor of Formula LIV(“Inh.4”) (pacritinib). The y-axis (“Effect”) is given in units of Fa(fraction affected) and the x-axis (“Dose”) is given in linear units ofμM.

FIG. 95 illustrates a quantitative comparison obtained by in vivoanalysis of early thrombus dynamics in a humanized mouse laser injurymodel using three BTK inhibitors at a concentration 1 μM.

FIG. 96 illustrates the results of GPVI platelet aggregation studies ofFormula XVIII (IC50=1.15 μM) and Formula XX-A (ibrutinib, IC50=0.13 μM).

FIG. 97 illustrates the results of GPVI platelet aggregation studies ofFormula XVIII and Formula XX-A (ibrutinib).

FIG. 98 shows NK cell degranulation results. The percentage ofCD56⁺/CD107a⁺ NK cells observed in whole blood after pretreatment for 1hour with the BTK inhibitors and stimulatation with MEC-1 cellsopsonised with obinutuzumab at 1 μg/mL for 4 hours (n=3) is shown.

FIG. 99 illustrates in vivo potency of Formula (XVIII) (labeled “BTKinhibitor”) and ibrutinib. Mice were gavaged at increasing drugconcentration and sacrificed at one time point (3 hours post-dose). BCRis stimulated with IgM and the expression of activation markers CD69 andCD86 are monitored by flow cytometry to determine EC₅₀values. Theresults show that Formula (XVIII) is more potent at inhibitingexpression of activation makers than ibrutinib.

FIG. 100 illustrates in vitro potency in whole blood of Formula (XVIII),ibrutinib and CC-292 in inhibition of signals through the B cellreceptor.

FIG. 101 illustrates EGF receptor phosphorylation in vitro for Formula(XVIII) and ibrutinib.

FIG. 102 illustrates the results of the clinical study of Formula(XVIII) (labeled “BTK inhibitor”) in CLL, which are shown in comparisonto the results reported for ibrutinib in FIG. 1A of Byrd, et al., N.Engl. J. Med. 2013, 369, 32-42. The results show that the BTK inhibitorof Formula (XVIII) causes a much smaller relative increase and muchfaster decrease in absolute lymphocyte count (ALC) relative to the BTKinhibitor ibrutinib. The sum of the product of greatest diameters (SPD)also decreases more rapidly during treatment with the BTK inhibitor thanwith the BTK inhibitor ibrutinib.

FIG. 103 shows overall response data shown by SPD of enlarged lymphnodes in CLL patients as a function of dose of the BTK inhibitor ofFormula (XVIII).

FIG. 104 shows a comparison of progression-free survival (PFS) in CLLpatients treated with the BTK inhibitor ibrutinib or the BTK inhibitorof Formula (XVIII). The ibrutinib data is taken from Byrd, et al., N.Engl. J. Med. 2013, 369, 32-42. CLL patients treated with Formula(XVIII) for at least 8 days are included.

FIG. 105 shows a comparison of number of patients at risk in CLLpatients treated with the BTK inhibitor ibrutinib or the BTK inhibitorof Formula (XVIII). CLL patients treated with Formula (XVIII) for atleast 8 days are included.

FIG. 106 shows a comparison of progression-free survival (PFS) in CLLpatients exhibiting the 17p deletion and treated with the BTK inhibitoribrutinib or the BTK inhibitor of Formula (XVIII). The ibrutinib data istaken from Byrd, et al., N. Engl. J. Med. 2013, 369, 32-42.

FIG. 107 shows a comparison of number of patients at risk in CLLpatients exhibiting the 17p deletion and treated with the BTK inhibitoribrutinib or the BTK inhibitor of Formula (XVIII). The ibrutinib data istaken from Byrd, et al., N. Engl. J. Med. 2013, 369, 32-42. CLL patientstreated with Formula (XVIII) for at least 8 days are included.

FIG. 108 shows improved BTK target occupancy of Formula (XVIII) at lowerdosage versus ibrutinib in relapsed/refractory CLL patients.

FIG. 109 shows the % change in myeloid-derived suppressor cell (MDSC)(monocytic) level over 28 days versus % ALC change at Cycle 1, day 28(C1D28) with trendlines.

FIG. 110 shows the % change in MDSC (monocytic) level over 28 daysversus % ALC change at Cycle 2, day 28 (C2D28) with trendlines.

FIG. 111 shows the % change in natural killer (NK) cell level over 28days versus % ALC change at Cycle 1, day 28 (C2D28) with trendlines.

FIG. 112 shows the % change in NK cell level over 28 days versus % ALCchange at Cycle 2, day 28 (C2D28) with trendlines.

FIG. 113 compares the % change in MDSC (monocytic) level and % change inNK cell level over 28 days versus % ALC change with the % change inlevel of CD4⁺ T cells, CD8⁺ T cells, CD4⁺/CD8⁺ T cell ratio, NK-T cells,PD-1⁺CD4⁺ T cells, and PD-1⁺CD8⁺ T cells, also versus % ALC change, atCycle 1 day 28 (C1D28). Trendlines are shown for % change in MDSC(monocytic) level and % change in NK cell level.

FIG. 114 compares the % change in MDSC (monocytic) level and % change inNK cell level over 28 days versus % ALC change with the % change inlevel of CD4⁺ T cells, CD8⁺ T cells, CD4⁺/CD8⁺ T cell ratio, NK-T cells,PD-1⁺CD4⁺ T cells, and PD-1⁺CD8⁺ T cells, also versus % ALC change, atCycle 2 day 28 (C2D28). Trendlines are shown for % change in MDSC(monocytic) level and % change in NK cell level.

FIG. 115 shows an update of the data presented in FIG. 102.

FIG. 116 shows an update of the data presented in FIG. 108, and includesBID dosing results.

FIG. 117 illustrates PFS for patients with 11p deletion.

FIG. 118 illustrates PFS across relapsed/refractory patients with 11pdeletion and with 17q deletion and no 11p deletion.

FIG. 119 illustrates PFS for patients with 17q deletion and no 11pdeletion.

FIG. 120 illustrates updated SPD results from the clinical study ofFormula (XVIII) in relapsed/refractory CLL patients.

FIG. 121 illustrates that treatment of CLL patients with Formula (XVIII)resulted in increased apoptosis.

FIG. 122 illustrates a decrease in CXCL12 levels observed in patientstreated with Formula (XVIII).

FIG. 123 illustrates a decrease in CCL2 levels observed in patientstreated with Formula (XVIII).

FIG. 124 illustrates BTK inhibitory effects on MDSCs.

FIG. 125 illustrates the dosing schema used with the KrasLA2 non-smallcell lung cancer (NSCLC) model.

BRIEF DESCRIPTION OF THE SEQUENCE LISTING

SEQ ID NO:1 is the heavy chain amino acid sequence of the anti-CD20monoclonal antibody rituximab.

SEQ ID NO:2 is the light chain amino acid sequence of the anti-CD20monoclonal antibody rituximab.

SEQ ID NO:3 is the heavy chain amino acid sequence of the anti-CD20monoclonal antibody obinutuzumab.

SEQ ID NO:4 is the light chain amino acid sequence of the anti-CD20monoclonal antibody obinutuzumab.

SEQ ID NO:5 is the variable heavy chain amino acid sequence of theanti-CD20 monoclonal antibody ofatumumab.

SEQ ID NO:6 is the variable light chain amino acid sequence of theanti-CD20 monoclonal antibody ofatumumab.

SEQ ID NO:7 is the Fab fragment heavy chain amino acid sequence of theanti-CD20 monoclonal antibody ofatumumab.

SEQ ID NO:8 is the Fab fragment light chain amino acid sequence of theanti-CD20 monoclonal antibody ofatumumab.

SEQ ID NO:9 is the heavy chain amino acid sequence of the anti-CD20monoclonal antibody veltuzumab.

SEQ ID NO:10 is the light chain amino acid sequence of the anti-CD20monoclonal antibody veltuzumab.

SEQ ID NO:11 is the heavy chain amino acid sequence of the anti-CD20monoclonal antibody tositumomab.

SEQ ID NO:12 is the light chain amino acid sequence of the anti-CD20monoclonal antibody tositumomab.

SEQ ID NO:13 is the heavy chain amino acid sequence of the anti-CD20monoclonal antibody ibritumomab.

SEQ ID NO:14 is the light chain amino acid sequence of the anti-CD20monoclonal antibody ibritumomab.

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this invention belongs. All patents and publicationsreferred to herein are incorporated by reference in their entireties.

The terms “co-administration,” “co-administering,” “administered incombination with,” “administering in combination with,” “simultaneous,”and “concurrent,” as used herein, encompass administration of two ormore active pharmaceutical ingredients (in a preferred embodiment of thepresent invention, for example, at least one JAK-2 inhibitor and atleast one BTK inhibitor) to a subject so that both active pharmaceuticalingredients and/or their metabolites are present in the subject at thesame time. Co-administration includes simultaneous administration inseparate compositions, administration at different times in separatecompositions, or administration in a composition in which two or moreactive pharmaceutical ingredients are present. Simultaneousadministration in separate compositions and administration in acomposition in which both agents are present are preferred.

The term “in vivo” refers to an event that takes place in a subject'sbody.

The term “in vitro” refers to an event that takes places outside of asubject's body. In vitro assays encompass cell-based assays in whichcells alive or dead are employed and may also encompass a cell-freeassay in which no intact cells are employed.

The term “effective amount” or “therapeutically effective amount” refersto that amount of a compound or combination of compounds as describedherein that is sufficient to effect the intended application including,but not limited to, disease treatment. A therapeutically effectiveamount may vary depending upon the intended application (in vitro or invivo), or the subject and disease condition being treated (e.g., theweight, age and gender of the subject), the severity of the diseasecondition, the manner of administration, etc. which can readily bedetermined by one of ordinary skill in the art. The term also applies toa dose that will induce a particular response in target cells (e.g., thereduction of platelet adhesion and/or cell migration). The specific dosewill vary depending on the particular compounds chosen, the dosingregimen to be followed, whether the compound is administered incombination with other compounds, timing of administration, the tissueto which it is administered, and the physical delivery system in whichthe compound is carried.

A “therapeutic effect” as that term is used herein, encompasses atherapeutic benefit and/or a prophylactic benefit. A prophylactic effectincludes delaying or eliminating the appearance of a disease orcondition, delaying or eliminating the onset of symptoms of a disease orcondition, slowing, halting, or reversing the progression of a diseaseor condition, or any combination thereof.

The terms “QD,” “qd,” or “q.d.” mean quaque die, once a day, or oncedaily. The terms “BID,” “bid,” or “b.i.d.” mean bis in die, twice a day,or twice daily. The terms “TID,” “tid,” or “t.i.d.” mean ter in die,three times a day, or three times daily. The terms “QID,” “qid,” or“q.i.d.” mean quater in die, four times a day, or four times daily.

The term “pharmaceutically acceptable salt” refers to salts derived froma variety of organic and inorganic counter ions known in the art.Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids. Preferred inorganic acids from whichsalts can be derived include, for example, hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid.Preferred organic acids from which salts can be derived include, forexample, acetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid andsalicylic acid. Pharmaceutically acceptable base addition salts can beformed with inorganic and organic bases. Inorganic bases from whichsalts can be derived include, for example, sodium, potassium, lithium,ammonium, calcium, magnesium, iron, zinc, copper, manganese andaluminum. Organic bases from which salts can be derived include, forexample, primary, secondary, and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic ion exchange resins. Specific examples include isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine, andethanolamine. In some embodiments, the pharmaceutically acceptable baseaddition salt is chosen from ammonium, potassium, sodium, calcium, andmagnesium salts. The term “cocrystal” refers to a molecular complexderived from a number of cocrystal formers known in the art. Unlike asalt, a cocrystal typically does not involve hydrogen transfer betweenthe cocrystal and the drug, and instead involves intermolecularinteractions, such as hydrogen bonding, aromatic ring stacking, ordispersive forces, between the cocrystal former and the drug in thecrystal structure.

“Pharmaceutically acceptable carrier” or “pharmaceutically acceptableexcipient” is intended to include any and all solvents, dispersionmedia, coatings, antibacterial and antifungal agents, isotonic andabsorption delaying agents, and inert ingredients. The use of suchpharmaceutically acceptable carriers or pharmaceutically acceptableexcipients for active pharmaceutical ingredients is well known in theart. Except insofar as any conventional pharmaceutically acceptablecarrier or pharmaceutically acceptable excipient is incompatible withthe active pharmaceutical ingredient, its use in the therapeuticcompositions of the invention is contemplated. Additional activepharmaceutical ingredients, such as other drugs, can also beincorporated into the described compositions and methods.

“Prodrug” is intended to describe a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound described herein. Thus, the term “prodrug” refers to aprecursor of a biologically active compound that is pharmaceuticallyacceptable. A prodrug may be inactive when administered to a subject,but is converted in vivo to an active compound, for example, byhydrolysis. The prodrug compound often offers the advantages ofsolubility, tissue compatibility or delayed release in a mammalianorganism (see, e.g., Bundgaard, H., Design of Prodrugs (1985) (Elsevier,Amsterdam). The term “prodrug” is also intended to include anycovalently bonded carriers, which release the active compound in vivowhen administered to a subject. Prodrugs of an active compound, asdescribed herein, may be prepared by modifying functional groups presentin the active compound in such a way that the modifications are cleaved,either in routine manipulation or in vivo, to yield the active parentcompound. Prodrugs include, for example, compounds wherein a hydroxy,amino or mercapto group is bonded to any group that, when the prodrug ofthe active compound is administered to a mammalian subject, cleaves toform a free hydroxy, free amino or free mercapto group, respectively.Examples of prodrugs include, but are not limited to, acetates, formatesand benzoate derivatives of an alcohol, various ester derivatives of acarboxylic acid, or acetamide, formamide and benzamide derivatives of anamine functional group in the active compound.

As used herein, the term “warhead” or “warhead group” refers to afunctional group present on a compound of the present invention whereinthat functional group is capable of covalently binding to an amino acidresidue present in the binding pocket of the target protein (such ascysteine, lysine, histidine, or other residues capable of beingcovalently modified), thereby irreversibly inhibiting the protein.

Unless otherwise stated, the chemical structures depicted herein areintended to include compounds which differ only in the presence of oneor more isotopically enriched atoms. For example, compounds where one ormore hydrogen atoms is replaced by deuterium or tritium, or wherein oneor more carbon atoms is replaced by ¹³C- or ¹⁴C-enriched carbons, arewithin the scope of this invention.

When ranges are used herein to describe, for example, physical orchemical properties such as molecular weight or chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included. Use of the term “about” whenreferring to a number or a numerical range means that the number ornumerical range referred to is an approximation within experimentalvariability (or within statistical experimental error), and thus thenumber or numerical range may vary. The variation is typically from 0%to 15%, preferably from 0% to 10%, more preferably from 0% to 5% of thestated number or numerical range. The term “comprising” (and relatedterms such as “comprise” or “comprises” or “having” or “including”)includes those embodiments such as, for example, an embodiment of anycomposition of matter, method or process that “consist of” or “consistessentially of” the described features.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to ten carbon atoms (e.g., (C₁₋₁₀)alkyl orC₁₋₁₀ alkyl). Whenever it appears herein, a numerical range such as “1to 10” refers to each integer in the given range—e.g., “1 to 10 carbonatoms” means that the alkyl group may consist of 1 carbon atom, 2 carbonatoms, 3 carbon atoms, etc., up to and including 10 carbon atoms,although the definition is also intended to cover the occurrence of theterm “alkyl” where no numerical range is specifically designated.Typical alkyl groups include, but are in no way limited to, methyl,ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl isobutyl,tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl,nonyl and decyl. The alkyl moiety may be attached to the rest of themolecule by a single bond, such as for example, methyl (Me), ethyl (Et),n-propyl (Pr), 1-methylethyl (isopropyl), n-butyl, n-pentyl,1,1-dimethylethyl (t-butyl) and 3-methylhexyl. Unless stated otherwisespecifically in the specification, an alkyl group is optionallysubstituted by one or more of substituents which are independentlyheteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano,trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —OR^(a),—SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂ whereeach R^(a) is independently hydrogen, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Alkylaryl” refers to an -(alkyl)aryl radical where aryl and alkyl areas disclosed herein and which are optionally substituted by one or moreof the substituents described as suitable substituents for aryl andalkyl respectively.

“Alkylhetaryl” refers to an -(alkyl)hetaryl radical where hetaryl andalkyl are as disclosed herein and which are optionally substituted byone or more of the substituents described as suitable substituents foraryl and alkyl respectively.

“Alkylheterocycloalkyl” refers to an -(alkyl) heterocycyl radical wherealkyl and heterocycloalkyl are as disclosed herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for heterocycloalkyl and alkyl respectively.

An “alkene” moiety refers to a group consisting of at least two carbonatoms and at least one carbon-carbon double bond, and an “alkyne” moietyrefers to a group consisting of at least two carbon atoms and at leastone carbon-carbon triple bond. The alkyl moiety, whether saturated orunsaturated, may be branched, straight chain, or cyclic.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one double bond, and having from two to ten carbon atoms (i.e.,(C₂₋₁₀)alkenyl or C₂₋₁₀ alkenyl). Whenever it appears herein, anumerical range such as “2 to 10” refers to each integer in the givenrange—e.g., “2 to 10 carbon atoms” means that the alkenyl group mayconsist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10carbon atoms. The alkenyl moiety may be attached to the rest of themolecule by a single bond, such as for example, ethenyl (i.e., vinyl),prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl and penta-1,4-dienyl.Unless stated otherwise specifically in the specification, an alkenylgroup is optionally substituted by one or more substituents which areindependently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy,halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂, whereeach R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Alkenyl-cycloalkyl” refers to an -(alkenyl)cycloalkyl radical wherealkenyl and cycloalkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for alkenyl and cycloalkyl respectively.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one triple bond, having from two to ten carbon atoms (i.e.,(C₂₋₁₀)alkynyl or C₂₋₁₀ alkynyl). Whenever it appears herein, anumerical range such as “2 to 10” refers to each integer in the givenrange—e.g., “2 to 10 carbon atoms” means that the alkynyl group mayconsist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10carbon atoms. The alkynyl may be attached to the rest of the molecule bya single bond, for example, ethynyl, propynyl, butynyl, pentynyl andhexynyl. Unless stated otherwise specifically in the specification, analkynyl group is optionally substituted by one or more substituentswhich independently are: alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,trifluoromethoxy, nitro, trimethylsilanyl, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂, whereeach R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Alkynyl-cycloalkyl” refers to an -(alkynyl)cycloalkyl radical wherealkynyl and cycloalkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for alkynyl and cycloalkyl respectively.

“Carboxaldehyde” refers to a —(C═O)H radical.

“Carboxyl” refers to a —(C═O)OH radical.

“Cyano” refers to a —CN radical.

“Cycloalkyl” refers to a monocyclic or polycyclic radical that containsonly carbon and hydrogen, and may be saturated, or partiallyunsaturated. Cycloalkyl groups include groups having from 3 to 10 ringatoms (i.e. (C₃₋₁₀)cycloalkyl or C₃₋₁₀ cycloalkyl). Whenever it appearsherein, a numerical range such as “3 to 10” refers to each integer inthe given range—e.g., “3 to 10 carbon atoms” means that the cycloalkylgroup may consist of 3 carbon atoms, etc., up to and including 10 carbonatoms. Illustrative examples of cycloalkyl groups include, but are notlimited to the following moieties: cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl,cyclononyl, cyclodecyl, norbornyl, and the like. Unless stated otherwisespecifically in the specification, a cycloalkyl group is optionallysubstituted by one or more substituents which independently are: alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano,trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —OR^(a),—SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂, whereeach R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Cycloalkyl-alkenyl” refers to a -(cycloalkyl)alkenyl radical wherecycloalkyl and alkenyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for cycloalkyl and alkenyl, respectively.

“Cycloalkyl-heterocycloalkyl” refers to a -(cycloalkyl)heterocycloalkylradical where cycloalkyl and heterocycloalkyl are as disclosed hereinand which are optionally substituted by one or more of the substituentsdescribed as suitable substituents for cycloalkyl and heterocycloalkyl,respectively.

“Cycloalkyl-heteroaryl” refers to a -(cycloalkyl)heteroaryl radicalwhere cycloalkyl and heteroaryl are as disclosed herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for cycloalkyl and heteroaryl, respectively.

The term “alkoxy” refers to the group —O-alkyl, including from 1 to 8carbon atoms of a straight, branched, cyclic configuration andcombinations thereof attached to the parent structure through an oxygen.Examples include, but are not limited to, methoxy, ethoxy, propoxy,isopropoxy, cyclopropyloxy and cyclohexyloxy. “Lower alkoxy” refers toalkoxy groups containing one to six carbons.

The term “substituted alkoxy” refers to alkoxy wherein the alkylconstituent is substituted (i.e., —O-(substituted alkyl)). Unless statedotherwise specifically in the specification, the alkyl moiety of analkoxy group is optionally substituted by one or more substituents whichindependently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy,halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)OR^(a) (where t is 1 or2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂, where eachR^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

The term “alkoxycarbonyl” refers to a group of the formula(alkoxy)(C═O)— attached through the carbonyl carbon wherein the alkoxygroup has the indicated number of carbon atoms. Thus a(C₁₋₆)alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbonatoms attached through its oxygen to a carbonyl linker. “Loweralkoxycarbonyl” refers to an alkoxycarbonyl group wherein the alkoxygroup is a lower alkoxy group.

The term “substituted alkoxycarbonyl” refers to the group (substitutedalkyl)-O—C(O)— wherein the group is attached to the parent structurethrough the carbonyl functionality. Unless stated otherwise specificallyin the specification, the alkyl moiety of an alkoxycarbonyl group isoptionally substituted by one or more substituents which independentlyare: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano,trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —OR^(a),—SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂, whereeach R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Acyl” refers to the groups (alkyl)-C(O)—, (aryl)-C(O)—,(heteroaryl)-C(O)—, (heteroalkyl)-C(O)— and (heterocycloalkyl)-C(O)—,wherein the group is attached to the parent structure through thecarbonyl functionality. If the R radical is heteroaryl orheterocycloalkyl, the hetero ring or chain atoms contribute to the totalnumber of chain or ring atoms. Unless stated otherwise specifically inthe specification, the alkyl, aryl or heteroaryl moiety of the acylgroup is optionally substituted by one or more substituents which areindependently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy,halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂, whereeach R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Acyloxy” refers to a R(C═O)O— radical wherein R is alkyl, aryl,heteroaryl, heteroalkyl or heterocycloalkyl, which are as describedherein. If the R radical is heteroaryl or heterocycloalkyl, the heteroring or chain atoms contribute to the total number of chain or ringatoms. Unless stated otherwise specifically in the specification, the Rof an acyloxy group is optionally substituted by one or moresubstituents which independently are: alkyl, heteroalkyl, alkenyl,alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,trifluoromethoxy, nitro, trimethylsilanyl, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂, whereeach R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Amino” or “amine” refers to a —N(R^(a))₂ radical group, where eachR^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, unless statedotherwise specifically in the specification. When a —N(R^(a))₂ group hastwo R^(a) substituents other than hydrogen, they can be combined withthe nitrogen atom to form a 4-, 5-, 6- or 7-membered ring. For example,—N(R^(a))₂ is intended to include, but is not limited to, 1-pyrrolidinyland 4-morpholinyl. Unless stated otherwise specifically in thespecification, an amino group is optionally substituted by one or moresubstituents which independently are: alkyl, heteroalkyl, alkenyl,alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,trifluoromethoxy, nitro, trimethylsilanyl, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂, whereeach R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

The term “substituted amino” also refers to N-oxides of the groups—NHR^(d), and NR^(d)R^(d) each as described above. N-oxides can beprepared by treatment of the corresponding amino group with, forexample, hydrogen peroxide or m-chloroperoxybenzoic acid.

“Amide” or “amido” refers to a chemical moiety with formula —C(O)N(R)₂or —NHC(O)R, where R is selected from the group consisting of hydrogen,alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) andheteroalicyclic (bonded through a ring carbon), each of which moiety mayitself be optionally substituted. The R₂ of —N(R)₂ of the amide mayoptionally be taken together with the nitrogen to which it is attachedto form a 4-, 5-, 6- or 7-membered ring. Unless stated otherwisespecifically in the specification, an amido group is optionallysubstituted independently by one or more of the substituents asdescribed herein for alkyl, cycloalkyl, aryl, heteroaryl, orheterocycloalkyl. An amide may be an amino acid or a peptide moleculeattached to a compound disclosed herein, thereby forming a prodrug. Theprocedures and specific groups to make such amides are known to those ofskill in the art and can readily be found in seminal sources such asGreene and Wuts, Protective Groups in Organic Synthesis, 3^(rd) Ed.,John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein byreference in its entirety.

“Aromatic” or “aryl” or “Ar” refers to an aromatic radical with six toten ring atoms (e.g., C₆-C₁₀ aromatic or C₆-C₁₀ aryl) which has at leastone ring having a conjugated pi electron system which is carbocyclic(e.g., phenyl, fluorenyl, and naphthyl). Bivalent radicals formed fromsubstituted benzene derivatives and having the free valences at ringatoms are named as substituted phenylene radicals. Bivalent radicalsderived from univalent polycyclic hydrocarbon radicals whose names endin “-yl” by removal of one hydrogen atom from the carbon atom with thefree valence are named by adding “-idene” to the name of thecorresponding univalent radical, e.g., a naphthyl group with two pointsof attachment is termed naphthylidene. Whenever it appears herein, anumerical range such as “6 to 10” refers to each integer in the givenrange; e.g., “6 to 10 ring atoms” means that the aryl group may consistof 6 ring atoms, 7 ring atoms, etc., up to and including 10 ring atoms.The term includes monocyclic or fused-ring polycyclic (i.e., rings whichshare adjacent pairs of ring atoms) groups. Unless stated otherwisespecifically in the specification, an aryl moiety is optionallysubstituted by one or more substituents which are independently alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano,trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —OR^(a),—SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂, whereeach R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Aralkyl” or “arylalkyl” refers to an (aryl)alkyl-radical where aryl andalkyl are as disclosed herein and which are optionally substituted byone or more of the substituents described as suitable substituents foraryl and alkyl respectively.

“Ester” refers to a chemical radical of formula —COOR, where R isselected from the group consisting of alkyl, cycloalkyl, aryl,heteroaryl (bonded through a ring carbon) and heteroalicyclic (bondedthrough a ring carbon). The procedures and specific groups to makeesters are known to those of skill in the art and can readily be foundin seminal sources such as Greene and Wuts, Protective Groups in OrganicSynthesis, 3^(rd) Ed., John Wiley & Sons, New York, N.Y., 1999, which isincorporated herein by reference in its entirety. Unless statedotherwise specifically in the specification, an ester group isoptionally substituted by one or more substituents which independentlyare: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano,trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —OR^(a),—SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂, whereeach R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Fluoroalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more fluoro radicals, as defined above, forexample, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, and the like. The alkyl part of thefluoroalkyl radical may be optionally substituted as defined above foran alkyl group.

“Halo,” “halide,” or, alternatively, “halogen” is intended to meanfluoro, chloro, bromo or iodo. The terms “haloalkyl,” “haloalkenyl,”“haloalkynyl,” and “haloalkoxy” include alkyl, alkenyl, alkynyl andalkoxy structures that are substituted with one or more halo groups orwith combinations thereof. For example, the terms “fluoroalkyl” and“fluoroalkoxy” include haloalkyl and haloalkoxy groups, respectively, inwhich the halo is fluorine.

“Heteroalkyl,” “heteroalkenyl,” and “heteroalkynyl” refer to optionallysubstituted alkyl, alkenyl and alkynyl radicals and which have one ormore skeletal chain atoms selected from an atom other than carbon, e.g.,oxygen, nitrogen, sulfur, phosphorus or combinations thereof. Anumerical range may be given—e.g., C₁-C₄ heteroalkyl which refers to thechain length in total, which in this example is 4 atoms long. Aheteroalkyl group may be substituted with one or more substituents whichindependently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy,halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂, whereeach R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Heteroalkylaryl” refers to an -(heteroalkyl)aryl radical whereheteroalkyl and aryl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heteroalkyl and aryl, respectively.

“Heteroalkylheteroaryl” refers to an -(heteroalkyl)heteroaryl radicalwhere heteroalkyl and heteroaryl are as disclosed herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for heteroalkyl and heteroaryl, respectively.

“Heteroalkylheterocycloalkyl” refers to an-(heteroalkyl)heterocycloalkyl radical where heteroalkyl andheterocycloalkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heteroalkyl and heterocycloalkyl, respectively.

“Heteroalkylcycloalkyl” refers to an -(heteroalkyl)cycloalkyl radicalwhere heteroalkyl and cycloalkyl are as disclosed herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for heteroalkyl and cycloalkyl, respectively.

“Heteroaryl” or “heteroaromatic” or “HetAr” refers to a 5- to18-membered aromatic radical (e.g., C₅-C₁₃ heteroaryl) that includes oneor more ring heteroatoms selected from nitrogen, oxygen and sulfur, andwhich may be a monocyclic, bicyclic, tricyclic or tetracyclic ringsystem. Whenever it appears herein, a numerical range such as “5 to 18”refers to each integer in the given range—e.g., “5 to 18 ring atoms”means that the heteroaryl group may consist of 5 ring atoms, 6 ringatoms, etc., up to and including 18 ring atoms. Bivalent radicalsderived from univalent heteroaryl radicals whose names end in “-yl” byremoval of one hydrogen atom from the atom with the free valence arenamed by adding “-idene” to the name of the corresponding univalentradical—e.g., a pyridyl group with two points of attachment is apyridylidene. A N-containing “heteroaromatic” or “heteroaryl” moietyrefers to an aromatic group in which at least one of the skeletal atomsof the ring is a nitrogen atom. The polycyclic heteroaryl group may befused or non-fused. The heteroatom(s) in the heteroaryl radical areoptionally oxidized. One or more nitrogen atoms, if present, areoptionally quaternized. The heteroaryl may be attached to the rest ofthe molecule through any atom of the ring(s). Examples of heteroarylsinclude, but are not limited to, azepinyl, acridinyl, benzimidazolyl,benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl,benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl,benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,benzoxazolyl, benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl,benzopyranonyl, benzofuranyl, benzofuranonyl, benzofurazanyl,benzothiazolyl, benzothienyl(benzothiophenyl),benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl,pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl,pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl,quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e.thienyl). Unless stated otherwise specifically in the specification, aheteroaryl moiety is optionally substituted by one or more substituentswhich are independently: alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)₁R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or PO₃(R^(a))₂, where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

Substituted heteroaryl also includes ring systems substituted with oneor more oxide (—O—) substituents, such as, for example, pyridinylN-oxides.

“Heteroarylalkyl” refers to a moiety having an aryl moiety, as describedherein, connected to an alkylene moiety, as described herein, whereinthe connection to the remainder of the molecule is through the alkylenegroup.

“Heterocycloalkyl” refers to a stable 3- to 18-membered non-aromaticring radical that comprises two to twelve carbon atoms and from one tosix heteroatoms selected from nitrogen, oxygen and sulfur. Whenever itappears herein, a numerical range such as “3 to 18” refers to eachinteger in the given range—e.g., “3 to 18 ring atoms” means that theheterocycloalkyl group may consist of 3 ring atoms, 4 ring atoms, etc.,up to and including 18 ring atoms. Unless stated otherwise specificallyin the specification, the heterocycloalkyl radical is a monocyclic,bicyclic, tricyclic or tetracyclic ring system, which may include fusedor bridged ring systems. The heteroatoms in the heterocycloalkyl radicalmay be optionally oxidized. One or more nitrogen atoms, if present, areoptionally quaternized. The heterocycloalkyl radical is partially orfully saturated. The heterocycloalkyl may be attached to the rest of themolecule through any atom of the ring(s). Examples of suchheterocycloalkyl radicals include, but are not limited to, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification, a heterocycloalkyl moiety is optionally substituted byone or more substituents which independently are: alkyl, heteroalkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or PO₃(R^(a))₂, where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Heterocycloalkyl” also includes bicyclic ring systems wherein onenon-aromatic ring, usually with 3 to 7 ring atoms, contains at least 2carbon atoms in addition to 1-3 heteroatoms independently selected fromoxygen, sulfur, and nitrogen, as well as combinations comprising atleast one of the foregoing heteroatoms; and the other ring, usually with3 to 7 ring atoms, optionally contains 1-3 heteroatoms independentlyselected from oxygen, sulfur, and nitrogen and is not aromatic.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Isomers” are different compounds that have the same molecular formula.“Stereoisomers” are isomers that differ only in the way the atoms arearranged in space—i.e., having a different stereochemical configuration.“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is a“racemic” mixture. The term “(±)” is used to designate a racemic mixturewhere appropriate. “Diastereoisomers” are stereoisomers that have atleast two asymmetric atoms, but which are not mirror-images of eachother. The absolute stereochemistry is specified according to theCahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer thestereochemistry at each chiral carbon can be specified by either (R) or(S). Resolved compounds whose absolute configuration is unknown can bedesignated (+) or (−) depending on the direction (dextro- orlevorotatory) which they rotate plane polarized light at the wavelengthof the sodium D line. Certain of the compounds described herein containone or more asymmetric centers and can thus give rise to enantiomers,diastereomers, and other stereoisomeric forms that can be defined, interms of absolute stereochemistry, as (R) or (S). The present chemicalentities, pharmaceutical compositions and methods are meant to includeall such possible isomers, including racemic mixtures, optically pureforms and intermediate mixtures. Optically active (R)- and (S)-isomerscan be prepared using chiral synthons or chiral reagents, or resolvedusing conventional techniques. When the compounds described hereincontain olefinic double bonds or other centers of geometric asymmetry,and unless specified otherwise, it is intended that the compoundsinclude both E and Z geometric isomers.

“Enantiomeric purity” as used herein refers to the relative amounts,expressed as a percentage, of the presence of a specific enantiomerrelative to the other enantiomer. For example, if a compound, which maypotentially have an (R)- or an (S)-isomeric configuration, is present asa racemic mixture, the enantiomeric purity is about 50% with respect toeither the (R)- or (S)-isomer. If that compound has one isomeric formpredominant over the other, for example, 80% (S)-isomer and 20%(R)-isomer, the enantiomeric purity of the compound with respect to the(S)-isomeric form is 80%. The enantiomeric purity of a compound can bedetermined in a number of ways known in the art, including but notlimited to chromatography using a chiral support, polarimetricmeasurement of the rotation of polarized light, nuclear magneticresonance spectroscopy using chiral shift reagents which include but arenot limited to lanthanide containing chiral complexes or Pirkle'sreagents, or derivatization of a compounds using a chiral compound suchas Mosher's acid followed by chromatography or nuclear magneticresonance spectroscopy.

In preferred embodiments, the enantiomerically enriched composition hasa higher potency with respect to therapeutic utility per unit mass thandoes the racemic mixture of that composition. Enantiomers can beisolated from mixtures by methods known to those skilled in the art,including chiral high pressure liquid chromatography (HPLC) and theformation and crystallization of chiral salts; or preferred enantiomerscan be prepared by asymmetric syntheses. See, for example, Jacques, etal., Enantiomers, Racemates and Resolutions, Wiley Interscience, NewYork (1981); E. L. Eliel, Stereochemistry of Carbon Compounds,McGraw-Hill, New York (1962); and E. L. Eliel and S. H. Wilen,Stereochemistry of Organic Compounds, Wiley-Interscience, New York(1994).

The terms “enantiomerically enriched” and “non-racemic,” as used herein,refer to compositions in which the percent by weight of one enantiomeris greater than the amount of that one enantiomer in a control mixtureof the racemic composition (e.g., greater than 1:1 by weight). Forexample, an enantiomerically enriched preparation of the (S)-enantiomer,means a preparation of the compound having greater than 50% by weight ofthe (S)-enantiomer relative to the (R)-enantiomer, such as at least 75%by weight, or such as at least 80% by weight. In some embodiments, theenrichment can be significantly greater than 80% by weight, providing a“substantially enantiomerically enriched” or a “substantiallynon-racemic” preparation, which refers to preparations of compositionswhich have at least 85% by weight of one enantiomer relative to otherenantiomer, such as at least 90% by weight, or such as at least 95% byweight. The terms “enantiomerically pure” or “substantiallyenantiomerically pure” refers to a composition that comprises at least98% of a single enantiomer and less than 2% of the opposite enantiomer.

“Moiety” refers to a specific segment or functional group of a molecule.Chemical moieties are often recognized chemical entities embedded in orappended to a molecule.

“Tautomers” are structurally distinct isomers that interconvert bytautomerization. “Tautomerization” is a form of isomerization andincludes prototropic or proton-shift tautomerization, which isconsidered a subset of acid-base chemistry. “Prototropictautomerization” or “proton-shift tautomerization” involves themigration of a proton accompanied by changes in bond order, often theinterchange of a single bond with an adjacent double bond. Wheretautomerization is possible (e.g., in solution), a chemical equilibriumof tautomers can be reached. An example of tautomerization is keto-enoltautomerization. A specific example of keto-enol tautomerization is theinterconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-onetautomers. Another example of tautomerization is phenol-ketotautomerization. A specific example of phenol-keto tautomerization isthe interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers.

A “leaving group or atom” is any group or atom that will, under selectedreaction conditions, cleave from the starting material, thus promotingreaction at a specified site. Examples of such groups, unless otherwisespecified, include halogen atoms and mesyloxy, p-nitrobenzensulphonyloxyand tosyloxy groups.

“Protecting group” is intended to mean a group that selectively blocksone or more reactive sites in a multifunctional compound such that achemical reaction can be carried out selectively on another unprotectedreactive site and the group can then be readily removed or deprotectedafter the selective reaction is complete. A variety of protecting groupsare disclosed, for example, in T. H. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, Third Edition, John Wiley &Sons, New York (1999).

“Solvate” refers to a compound in physical association with one or moremolecules of a pharmaceutically acceptable solvent.

“Substituted” means that the referenced group may have attached one ormore additional groups, radicals or moieties individually andindependently selected from, for example, acyl, alkyl, alkylaryl,cycloalkyl, aralkyl, aryl, carbohydrate, carbonate, heteroaryl,heterocycloalkyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio,arylthio, cyano, halo, carbonyl, ester, thiocarbonyl, isocyanato,thiocyanato, isothiocyanato, nitro, oxo, perhaloalkyl, perfluoroalkyl,phosphate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate,urea, and amino, including mono- and di-substituted amino groups, andprotected derivatives thereof. The substituents themselves may besubstituted, for example, a cycloalkyl substituent may itself have ahalide substituent at one or more of its ring carbons. The term“optionally substituted” means optional substitution with the specifiedgroups, radicals or moieties.

“Sulfanyl” refers to groups that include —S-(optionally substitutedalkyl), —S-(optionally substituted aryl), —S-(optionally substitutedheteroaryl) and —S-(optionally substituted heterocycloalkyl).

“Sulfinyl” refers to groups that include —S(O)—H, —S(O)-(optionallysubstituted alkyl), —S(O)-(optionally substituted amino),—S(O)-(optionally substituted aryl), —S(O)-(optionally substitutedheteroaryl) and —S(O)-(optionally substituted heterocycloalkyl).

“Sulfonyl” refers to groups that include —S(O₂)—H, —S(O₂)-(optionallysubstituted alkyl), —S(O₂)-(optionally substituted amino),—S(O₂)-(optionally substituted aryl), —S(O₂)-(optionally substitutedheteroaryl), and —S(O₂)-(optionally substituted heterocycloalkyl).

“Sulfonamidyl” or “sulfonamido” refers to a —S(═O)₂—NRR radical, whereeach R is selected independently from the group consisting of hydrogen,alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) andheteroalicyclic (bonded through a ring carbon). The R groups in —NRR ofthe —S(═O)₂—NRR radical may be taken together with the nitrogen to whichit is attached to form a 4-, 5-, 6- or 7-membered ring. A sulfonamidogroup is optionally substituted by one or more of the substituentsdescribed for alkyl, cycloalkyl, aryl, heteroaryl, respectively.

“Sulfoxyl” refers to a —S(═O)₂OH radical.

“Sulfonate” refers to a —S(═O)₂—OR radical, where R is selected from thegroup consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded througha ring carbon) and heteroalicyclic (bonded through a ring carbon). Asulfonate group is optionally substituted on R by one or more of thesubstituents described for alkyl, cycloalkyl, aryl, heteroaryl,respectively.

Compounds of the invention also include crystalline and amorphous formsof those compounds, including, for example, polymorphs,pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (includinganhydrates), conformational polymorphs, and amorphous forms of thecompounds, as well as mixtures thereof. “Crystalline form” and“polymorph” are intended to include all crystalline and amorphous formsof the compound, including, for example, polymorphs, pseudopolymorphs,solvates, hydrates, unsolvated polymorphs (including anhydrates),conformational polymorphs, and amorphous forms, as well as mixturesthereof, unless a particular crystalline or amorphous form is referredto.

Co-Administration of Compounds

An aspect of the invention is a composition, such as a pharmaceuticalcomposition, comprising a combination of a PI3K inhibitor, a BTKinhibitor, and/or a JAK-2 inhbitor. Preferably, said compositioncomprises a combination of a BTK inhibitor and a JAK-2 inhibitor.

Another aspect is a kit containing any two or all three of a PI3Kinhibitor, a BTK inhibitor, and a JAK-2 inhibitor, wherein each of theinhibitors is formulated into a separate pharmaceutical composition, andwherein said separate pharmaceutical compositions are formulated forco-administration. Preferably, said kit contains a BTK inhibitor and aJAK-2 inhibitor.

Another aspect of the invention is a method of treating a disease orcondition in a subject, in particular a hyperproliferative disorder suchas leukemia, lymphoma or a solid tumor cancer in a subject, comprisingco-administering to the subject in need thereof a therapeuticallyeffective amount of a combination of a PI3K inhibitor, a BTK inhibitor,and/or a JAK-2 inhibitor. In an embodiment, the foregoing methodexhibits synergistic effects that may result in greater efficacy, lessside effects, the use of less active pharmaceutical ingredient toachieve a given clinical result, or other synergistic effects. Acombination of a BTK inhibitor and a JAK-2 inhibitor is a preferredembodiment. The pharmaceutical composition comprising the combination,and the kit, are both for use in treating such disease or condition.

In a preferred embodiment, the solid tumor cancer is selected from thegroup consisting of breast, lung, colorectal, thyroid, bone sarcoma, andstomach cancers.

In a preferred embodiment, the leukemia is selected from the groupconsisting of acute myelogenous leukemia (AML), chronic myelogenousleukemia (CML), acute lymphoblastic leukemia (ALL), B cell chroniclymphocytic leukemia (B-CLL), and chronic lymphoid leukemia (CLL).

In a preferred embodiment, the lymphoma is selected from the groupconsisting of Burkitt's lymphoma, mantle cell lymphoma, follicularlymphoma, indolent B-cell non-Hodgkin's lymphoma, histiocytic lymphoma,activated B-cell like diffuse large B cell lymphoma (DLBCL-ABC),germinal center B-cell like diffuse large B cell lymphoma (DLBCL-GCB),and diffuse large B cell lymphoma (DLBCL).

In an embodiment, the PI3K inhibitor is a PI3K-γ inhibitor.

In a preferred embodiment, the PI3K inhibitor is a PI3K-δ inhibitor.

In a preferred embodiment, the PI3K inhibitor is a PI3K-γ,δ inhibitor.

In an embodiment, the PI3K inhibitor is a selective PI3K inhibitor.

In an embodiment, the combination of the PI3K inhibitor, PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor with the BTKinhibitor is administered by oral, intravenous, intramuscular,intraperitoneal, subcutaneous or transdermal means.

In an embodiment, the PI3K inhibitor, PI3K-γ inhibitor, PI3K-δinhibitor, or PI3K-γ,δ inhibitor is in the form of a pharmaceuticallyacceptable salt, solvate, hydrate, complex, derivative, prodrug (such asan ester or phosphate ester), or cocrystal.

In an embodiment, the BTK inhibitor is in the form of a pharmaceuticallyacceptable salt, solvate, hydrate, complex, derivative, prodrug (such asan ester or phosphate ester), or cocrystal.

In an embodiment, the JAK-2 inhibitor is in the form of apharmaceutically acceptable salt, solvate, hydrate, complex, derivative,prodrug (such as an ester or phosphate ester), or cocrystal.

In an embodiment, the PI3K inhibitor, which is preferably selected fromthe group consisting of a PI3K-γ inhibitor, a PI3K-δ inhibitor, and aPI3K-γ,δ inhibitor, is administered to the subject before administrationof the BTK inhibitor.

In an embodiment, the PI3K inhibitor, which is preferably selected fromthe group consisting of a PI3K-γ inhibitor, a PI3K-δ inhibitor, and aPI3K-γ,δ inhibitor is administered concurrently with the administrationof the BTK inhibitor.

In an embodiment, the PI3K inhibitor, which is preferably selected fromthe group consisting of a PI3K-γ inhibitor, a PI3K-δ inhibitor, and aPI3K-γ,δ inhibitor is administered to the subject after administrationof the BTK inhibitor.

In an embodiment, the JAK-2 inhibitor is administered to the subjectbefore administration of the BTK inhibitor.

In an embodiment, the JAK-2 inhibitor is administered concurrently withthe administration of the BTK inhibitor.

In an embodiment, the JAK-2 inhibitor is administered to the subjectafter administration of the BTK inhibitor.

In an embodiment, the JAK-2 inhibitor is administered to the subjectafter administration of the BTK inhibitor.

In an embodiment, the JAK-2 inhibitor is administered to the subjectbefore administration of the PI3K inhibitor.

In an embodiment, the JAK-2 inhibitor is administered concurrently withthe administration of the PI3K inhibitor.

In a preferred embodiment, the BTK inhibitor, JAK-2 inhibitor, and/orPI3K inhibitor are administered concurrently.

In a preferred embodiment, the subject is a mammal, such as a human. Inan embodiment, the subject is a human. In an embodiment, the subject isa companion animal. In an embodiment, the subject is a canine, feline,or equine.

PI3K Inhibitors

The PI3K inhibitor may be any PI3K inhibitor known in the art. Inparticular, it is one of the PI3K inhibitors described in more detail inthe following paragraphs. Preferably, it is a PI3K inhibitor selectedfrom the group consisting of a PI3K-γ inhibitor, a PI3K-δ inhibitor, anda PI3K-γ,δ inhibitor. In one specific embodiment, it is a PI3K-δinhibitor.

In an embodiment, the PI3K inhibitor, which is preferably selected fromthe group consisting of a PI3K-γ inhibitor, a PI3K-δ inhibitor, and aPI3K-γ,δ inhibitor, is a compound selected from the structures disclosedin U.S. Pat. Nos. 8,193,182 and 8,569,323, and U.S. Patent ApplicationPublication Nos. 2012/0184568 A1, 2013/0344061 A1, and 2013/0267521 A1,the disclosures of which are incorporated by reference herein. In anembodiment, the PI3K inhibitor (which may be a PI3K-γ inhibitor, PI3K-δinhibitor, or PI3K-γ,δ inhibitor) is a compound of Formula (I):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal orprodrug thereof, wherein:

-   Cy is aryl or heteroaryl substituted by 0 or 1 occurrences of R³ and    0, 1, 2, or 3 occurrences of R⁵;-   W_(b) ⁵ is CR⁸, CHR⁸, or N;-   R⁸ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,    alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano,    hydroxyl or nitro;-   B is hydrogen, alkyl, amino, heteroalkyl, cycloalkyl, heterocyclyl,    aryl, or heteroaryl, each of which is substituted with 0, 1, 2, 3,    or 4 occurrences of R²;-   each R² is independently alkyl, heteroalkyl, alkenyl, alkynyl,    cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl,    heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy,    alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl, nitro,    phosphate, urea, or carbonate;-   X is —(CH(R⁹))_(z)—;-   Y is —N(R⁹)—C(═O)—, —C(═O)—N(R⁹)—, —C(═O)—N(R⁹)—(CHR⁹)—,    —N(R⁹)—S(═O)—, —S(═O)—N(R⁹)—, S(═O)₂—N(R⁹)—, —N(R⁹)—C(═O)—N(R⁹) or    —N(R⁹)S(═O)₂—;-   z is an integer of 1, 2, 3, or 4;-   R³ is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,    fluoroalkyl, heteroalkyl, alkoxy, amido, amino, acyl, acyloxy,    sulfinyl, sulfonyl, sulfoxide, sulfone, sulfonamido, halo, cyano,    aryl, heteroaryl, hydroxyl, or nitro;-   each R⁵ is independently alkyl, alkenyl, alkynyl, cycloalkyl,    heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo,    cyano, hydroxyl, or nitro;-   each R⁹ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl,    or heteroalkyl; or two adjacent occurrences of R⁹ together with the    atoms to which they are attached form a 4- to 7-membered ring;-   W_(d) is heterocyclyl, aryl, cycloalkyl, or heteroaryl, each of    which is substituted with one or more R¹⁰, R¹¹, R¹² or R¹³, and-   R¹⁰, R¹¹, R¹² and R¹³ are each independently hydrogen, alkyl,    heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,    arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy,    amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo,    cyano, hydroxyl, nitro, phosphate, urea, carbonate or NR′R″ wherein    R′ and R″ are taken together with nitrogen to form a cyclic moiety.

In an embodiment, the PI3K inhibitor (which may be a PI3K-γ inhibitor,PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is a compound of Formula (I-1):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, wherein:

-   B is a moiety of Formula (II-A):

-   W_(c) is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl;-   q is an integer of 0, 1, 2, 3, or 4;-   X is a bond or —(CH(R⁹))_(z)—, and z is an integer of 1, 2, 3 or 4;-   Y is a bond, —N(R⁹)—, —O—, —S—, —S(═O)—, —S(═O)₂, —C(═O)—,    —C(═O)(CHR⁹)_(z)—, —N(R⁹)—C(═O)—, —N(R⁹)—C(═O)NH— or —N(R⁹)C(R⁹)₂—;-   z is an integer of 1, 2, 3, or 4;-   W_(d) is:

-   X₁, X₂ and X₃ are each independently C, CR¹³ or N; and X₄, X₅ and X₆    are each independently N, NH, CR¹³, S or O;-   R¹ is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, amido,    alkoxycarbonyl, sulfonamido, halo, cyano, or nitro;-   R² is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,    heteroaryl, heteroarylalkyl, alkoxy, amino, halo, cyano, hydroxy or    nitro;-   R³ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,    heterocycloalkyl, alkoxy, amido, amino, alkoxycarbonyl sulfonamido,    halo, cyano, hydroxy or nitro; and-   each instance of R⁹ is independently hydrogen, alkyl, or    heterocycloalkyl.

In a preferred embodiment, the PI3K inhibitor (which may be a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is a compound ofFormula (III):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, where B is a moiety of Formula (II-A),

-   R² is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,    heteroaryl, heteroarylalkyl, alkoxy, amino, halo, cyano, hydroxy or    nitro; and-   R⁹ is hydrogen, alkyl, or heterocycloalkyl.

In a preferred embodiment, the PI3K-γ,δ inhibitor is a compound ofFormula (III-A):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. Formula (III-A) is also known as IPI-145 or duvelisib(Infinity Pharmaceuticals) and has been studied at doses of 5 mg and 25mg in clinical trials, including those described in Flinn, et al.,Blood, 2014, 124, 802, and O'Brien, et al., Blood, 2014, 124, 3334.

In a preferred embodiment, the PI3K inhibitor is a compound of Formula(IV):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof.

In a preferred embodiment, the PI3K inhibitor is(S)-3-(1-((9H-purin-6-yl)amino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-oneor a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof.

In a preferred embodiment, the PI3K inhibitor is(S)-3-amino-N-(1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)pyrazine-2-carboxamideor a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof.

In an embodiment, the PI3K inhibitor (which may be a PI3K-γ inhibitor,PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is a compound selected from thestructures disclosed in U.S. Pat. Nos. 8,193,199, 8,586,739, and8,901,135, the disclosure of each of which is incorporated by referenceherein. In an embodiment, the PI3K inhibitor or PI3K-δ inhibitor is acompound of Formula (V):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, wherein:

-   X¹ is C(R⁹) or N;-   X² is C(R¹⁰) or N;-   Y is N(R¹¹), O or S;-   Z is CR⁸ or N;-   n is 0, 1, 2 or 3;-   R¹ is a direct-bonded or oxygen-linked saturated, partially    saturated or unsaturated 5-, 6- or 7-membered monocyclic ring    containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, but    containing no more than one 0 or S, wherein the available carbon    atoms of the ring are substituted by 0, 1 or 2 oxo or thioxo groups,    wherein the ring is substituted by 0 or 1 R² substituents, and the    ring is additionally substituted by 0, 1, 2 or 3 substituents    independently selected from halo, nitro, cyano, (C₁₋₄)alkyl,    O(C₁₋₄)alkyl, O(C₁₋₄)haloalkyl, NHC₁₋₄, N((C₁₋₄)alkyl)(C₁₋₄)alkyl    and (C₁₋₄)haloalkyl;-   R² is selected from halo, (C₁₋₄)haloalkyl, cyano, nitro,    —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),    —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a).    —OC(═O)N(R^(a))S(═O)₂R^(a), —O(C₂₋₆)alkylNR^(a)R^(a),    —O(C₂₋₆)alkylOR^(a), —SR^(a), OS(═O)R^(a), —S(═O)₂R^(a),    —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    —NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),    —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),    —N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)(C₂₋₆    alkylNR^(a)R^(a) and —NR^(a)(C₂₋₆)alkylOR^(a); or R² is selected    from (C₁₋₆)alkyl, phenyl, benzyl, heteroaryl, heterocycle,    —((C₁₋₃)alkyl)heteroaryl, —((C₁₋₃)alkyl)heterocycle,    —O((C₁₋₃)alkyl)heteroaryl, —O((C₁₋₃)alkyl)heterocycle,    —NR^(a)((C₁₋₃)alkyl)heteroaryl, —NR^(a)((C₁₋₃)alkyl)heterocycle,    —(C₁₋₃)alkyl)phenyl, —O((C₁₋₃)alkyl)phenyl and    —NR^(a)((C₁₋₃)alkyl)phenyl all of which are substituted by 0, 1, 2    or 3 substituents selected from (C₁₋₄)haloalkyl, O(C₁₋₄)alkyl, Br,    Cl, F, I and (C₁₋₄)alkyl;-   R³ is selected from H, halo, (C₁₋₄)haloalkyl, cyano, nitro,    —C(═O)R^(a), —C(═O)R^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),    —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R²,    —O(C₂₋₆)alkylNR^(a)R^(a), —O(C₂₋₆)alkylOR^(a), —SR^(a), —S(═O)R^(a),    —S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    —NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),    —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))    S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)NR^(a)R^(a),    —NR^(a)(C₂₋₆)alkylOR^(a), (C₁₋₆)alkyl, phenyl, benzyl, heteroaryl    and heterocycle, wherein the (C₁₋₆)alkyl, phenyl, benzyl, heteroaryl    and heterocycle are additionally substituted by 0, 1, 2 or 3    substituents selected from (C₁₋₆)haloalkyl, O(C₁₋₆)alkyl, Br, Cl, F,    I and (C₁₋₆)alkyl;-   R⁴ is, independently, in each instance, halo, nitro, cyano,    (C₁₋₄)alkyl, O(C₁₋₄)alkyl, O(C₁₋₄)haloalkyl, NH(C₁₋₄)alkyl,    N((C₁₋₄)alkyl)(C₁₋₄)alkyl or (C₁₋₄)haloalkyl;-   R⁵ is, independently, in each instance, H, halo, (C₁₋₆)alkyl,    (C₁₋₄)haloalkyl, or (C₁₋₆)alkyl substituted by 1, 2 or 3    substituents selected from halo, cyano, OH, O(C₁₋₄)alkyl,    (C₁₋₄)alkyl, (C₁₋₃)haloalkyl, O(C₁₋₄)alkyl, NH₂, NHC₁₋₄)alkyl,    N(C₁₋₄)alkyl(C₁₋₄)alkyl; or both R⁵ groups together form a    (C₃₋₆)spiroalkyl substituted by 0, 1, 2 or 3 substituents selected    from halo, cyano, OH, O(C₁₋₄)alkyl, (C₁₋₄)alkyl, (C₁₋₃)haloalkyl,    O(C₁₋₄)alkyl, NH₂, NH(C₁₋₄)alkyl, N((C₁₋₄)alkyl)(C₁₋₄)alkyl;-   R⁶ is selected from H, halo, (C₁₋₆)alkyl, (C₁₋₄)haloalkyl, cyano,    nitro, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),    —C(═NR^(a))NR^(a)R^(a), —S(═O)R^(a), —S(═O)₂R^(a),    —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a);-   R⁷ is selected from H, halo, (C₁₋₆)alkyl, (C₁₋₄)haloalkyl, cyano,    nitro, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),    —C(═NR^(a))NR^(a)R^(a), —S(═O)R^(a), —S(═O)₂R^(a),    —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a);-   R⁸ is selected from H, (C₁₋₆)haloalkyl, Br, Cl, F, I, OR^(a),    NR^(a)R^(a), (C₁₋₆)alkyl, phenyl, benzyl, heteroaryl and    heterocycle, wherein the (C₁₋₆)alkyl, phenyl, benzyl, heteroaryl and    heterocycle are additionally substituted by 0, 1, 2 or 3    substituents selected from (C₁₋₆)haloalkyl, O(C₁₋₆)alkyl, Br, Cl, F,    I and (C₁₋₆)alkyl;-   R⁹ is selected from H, halo, (C₁₋₄)haloalkyl, cyano, nitro,    —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a)C(═NR^(a))NR^(a)R^(a),    —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a),    —OC(═O)N(R^(a))S(═O)₂R^(a), —O(C₂₋₆)alkylOR^(a), —SR^(a),    —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a),    —S(═O)₂N(R^(a))C(═O)R^(a), —S(═O)₂N(R^(a))C(═O)OR^(a),    —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), NR^(a)R^(a), —N(R^(a))C(═O)R^(a),    —N(R^(a))C(═O)OR^(a),    —N(R^(a))C(O)NR^(a)R^(a)N(R^(a)C(═NR^(a))NR^(a)R^(a),    —N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)(C₂₋₆    alkylNR^(a)R^(a), —NR^(a)(C₁₋₆)alkyl, phenyl, benzyl, heteroaryl and    heterocycle, wherein the (C₁₋₆ alkyl, phenyl, benzyl, heteroaryl and    heterocycle are additionally substituted by 0, 1, 2 or 3    substituents selected from halo, (C₁₋₄)haloalkyl, cyano, nitro,    —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),    —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a),    —OC(═O)N(R^(a))S(═O)₂R^(a), —O(C₂₋₆)alkylNR^(a)R^(a),    —O(C₂₋₆)alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),    —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),    —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),    —N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),    —NR^(a)(C₂₋₆)alkylOR^(a), —NR^(a)(C₂₋₆)alkylOR^(a); or R⁹ is a    saturated, partially-saturated or unsaturated 5-, 6- or 7-membered    monocyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O    and S, but containing no more than one O or S, wherein the available    carbon atoms of the ring are substituted by 0, 1 or 2 oxo or thioxo    groups, wherein the ring is substituted by 0, 1, 2, 3 or 4    substituents selected from halo, (C₁₋₄)haloalkyl, cyano, nitro,    —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),    —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a),    —OC(═O)N(R^(a))S(═O)₂R^(a), —O(C₂₋₆)alkylNR^(a)R^(a),    —O(C₂₋₆)alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),    —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    —NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),    —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),    —N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),    —NR^(a)(C₂₋₆)alkylNR^(a)R^(a) and —NR^(a)(C₂₋₆)alkylOR^(a);-   R¹⁰ is H, (C₁₋₃)alkyl, (C₁₋₃)haloalkyl, cyano, nitro, CO₂R^(a),    C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    —S(═O)R^(b), S(═O)₂R^(b) or S(═O)₂NR^(a)R^(a);-   R¹¹ is H or (C₁₋₄)alkyl;-   R^(a) is independently, at each instance, H or R^(b); and-   R^(b) is independently, at each instance, phenyl, benzyl or    (C₁₋₆)alkyl, the phenyl, benzyl and (C₁₋₆)alkyl being substituted by    0, 1, 2 or 3 substituents selected from halo, (C₁₋₄)alkyl,    (C₁₋₃)haloalkyl, —O(C₁₋₄)alkyl, —NH₂, —NHC₁₋₄)alkyl,    —N((C₁₋₄)alkyl)(C₁₋₄)alkyl.

In another embodiment, the PI3K inhibitor (which may be a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is a compound ofFormula (VI):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, wherein:

-   X¹ is C(R⁹) or N;-   X² is C(R¹⁰) or N;-   Y is N(R¹¹), O or S;-   Z is CR⁸ or N;-   R¹ is a direct-bonded or oxygen-linked saturated,    partially-saturated or unsaturated 5-, 6- or 7-membered monocyclic    ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, but    containing no more than one O or S, wherein the available carbon    atoms of the ring are substituted by 0, 1 or 2 oxo or thioxo groups,    wherein the ring is substituted by 0 or 1 R² substituents, and the    ring is additionally substituted by 0, 1, 2 or 3 substituents    independently selected from halo, nitro, cyano, (C₁₋₄)alkyl,    O(C₁₋₄)alkyl, O(C₁₋₄)haloalkyl, (NHC₁₋₄)alkyl, N(C₁₋₄    alkyl)(C₁₋₄)alkyl and (C₁₋₄)haloalkyl;-   R² is selected from halo, (C₁₋₄)haloalkyl, cyano, nitro,    —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),    —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a),    —OC(═O)N(R^(a))S(═O)₂R^(a), —O(C₂₋₆)alkylNR^(a)R^(a),    —O(C₂₋₆)alkylOR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a),    —S(═O)₂N(R^(a))C(═O)R^(a), —S(═O)₂N(R^(a))C(═O)OR^(a),    —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(a),    —N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)NR^(a)R^(a),    —N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(a),    —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)(C₂₋₆ alkylNR^(a)R^(a) and    —NR^(a)(C₂₋₆)alkylOR^(a); or R² is selected from (C₁₋₆)alkyl,    phenyl, benzyl, heteroaryl, heterocycle, —((C₁₋₃)alkyl)heteroaryl,    —((C₁₋₃)alkyl)heterocycle, —O((C₁₋₃)alkyl)heteroaryl,    —O((C₁₋₃)alkyl)heterocycle, —NR^(a)((C₁₋₃)alkyl)heteroaryl,    —NR^(a)((C₁₋₃)alkyl)heterocycle, —((C₁₋₃)alkyl)phenyl,    —O((C₁₋₃)alkyl)phenyl and —NR^(a)(C₁₋₃ alkyl)phenyl all of which are    substituted by 0, 1, 2 or 3 substituents selected from    (C₁₋₄)haloalkyl, O(C₁₋₄)alkyl, Br, Cl, F, I and (C₁₋₄)alkyl;-   R³ is selected from H, halo, (C₁₋₄)haloalkyl, cyano, nitro,    —C(═O)R^(a), —C(═O)OR^(a), C(═O)NR^(a)R^(a)C(═NR^(a))NR^(a),    —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a),    —OC(═O)N(R^(a))S(═O)₂R^(a), —O(C₂₋₆)alkylNR^(a)R^(a),    —O(C₂₋₆)alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),    —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),    —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))    S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)(C₂₋₆)alkylOR^(a),    (C₁₋₆)alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein the    (C₁₋₆)alkyl, phenyl, benzyl, heteroaryl and heterocycle are    additionally substituted by 0, 1, 2 or 3 substituents selected from    (C₁₋₆)haloalkyl, O(C₁₋₆)alkyl, Br, Cl, F, I and (C₁₋₆)alkyl;-   R⁵ is, independently, in each instance, H, halo, (C₁₋₆)alkyl,    (C₁₋₄)haloalkyl, or (C₁₋₆)alkyl substituted by 1, 2 or 3    substituents selected from halo, cyano, OH, O(C₁₋₄)alkyl,    (C₁₋₄)alkyl, (C₁₋₃)haloalkyl, O(C₁₋₄)alkyl, NH₂, (NHC₁₋₄)alkyl,    N(C₁₋₄)alkyl(C₁₋₄)alkyl; or both R⁵ groups together form a    C₃₋₆-spiroalkyl substituted by 0, 1, 2 or 3 substituents selected    from halo, cyano, OH, O(C₁₋₄)alkyl, (C₁₋₄)alkyl, (C₁₋₃)haloalkyl,    O(C₁₋₄)alkyl, NH₂, (NHC₁₋₄)alkyl, N((C₁₋₄)alkyl)(C₁₋₄)alkyl;-   R⁶ is selected from H, halo, (C₁₋₆)alkyl, (C₁₋₄)haloalkyl, cyano,    nitro, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),    —C(═NR^(a))NR^(a)R^(a), —S(═O)R^(a), —S(═O)₂R^(a),    —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a);-   R⁷ is selected from H, halo, (C₁₋₆)alkyl, (C₁₋₄)haloalkyl, cyano,    nitro, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),    —C(═NR^(a))NR^(a)R^(a), —S(═O)R^(a)S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a),    —S(═O)₂N(R^(a))C(═O)R^(a), —S(═O)₂N(R^(a))C(═O)OR^(a),    —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a);-   R⁸ is selected from H, (C₁₋₆)haloalkyl, Br, Cl, F, I, OR^(a),    NR^(a)R^(a), (C₁₋₆)alkyl, phenyl, benzyl, heteroaryl and    heterocycle, wherein the (C₁₋₆)alkyl, phenyl, benzyl, heteroaryl and    heterocycle are additionally substituted by 0, 1, 2 or 3    substituents selected from (C₁₋₆)haloalkyl, O(C₁₋₆ alkyl, Br, Cl, F,    I and (C₁₋₆)alkyl;-   R⁹ is selected from H, halo, (C₁₋₄)haloalkyl, cyano, nitro,    —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),    —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a), OC(═O)NR^(a)R^(a),    —OC(═O)N(R^(a))S(═O)₂R^(a), —O(C₂₋₆)alkylNR^(a)R^(a),    —O(C₂₋₆)alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),    —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    —NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),    —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),    —N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),    —NR^(a)(C₂₋₆)alkylNR^(a)R^(a), —NR^(a)(C₂₋₆)alkylOR^(a),    (C₁₋₆)alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein the    (C₁₋₆)alkyl, phenyl, benzyl, heteroaryl and heterocycle are    additionally substituted by 0, 1, 2 or 3 substituents selected from    halo, (C₁₋₄)haloalkyl, cyano, nitro, —C(═O)R^(a), —C(═O)OR^(a),    —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a),    —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a), —O(C₂₋₆)alkylOR^(a),    —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a),    —S(═O)₂N(R^(a))C(═O)R^(a), —S(═O)₂N(R^(a))C(═O)OR^(a),    —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), NR^(a)R^(a), —N(R^(a))C(═O)R^(a),    —N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)NR^(a)R^(a),    —N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(a),    —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)(C₂₋₆)alkylNR^(a),    —NR^(a)(C₂₋₆)alkylOR^(a); or R⁹ is a saturated, partially-saturated    or unsaturated 5-, 6- or 7-membered monocyclic ring containing 0, 1,    2, 3 or 4 atoms selected from N, O and S, but containing no more    than one O or S, wherein the available carbon atoms of the ring are    substituted by 0, 1 or 2 oxo or thioxo groups, wherein the ring is    substituted by 0, 1, 2, 3 or 4 substituents selected from halo,    (C₁₋₄)haloalkyl, cyano, nitro, —C(═O)R^(a), —C(═O)OR^(a),    —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a),    —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a), —O(C₂₋₆)alkylOR^(a),    —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a),    —S(═O)₂N(R^(a))C(═O)R^(a), —S(═O)₂N(R^(a))C(═O)OR^(a),    —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(a),    —N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)NR^(a)R^(a),    —N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a)) S(═O)₂R^(a),    —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)(C₂₋₆ alkylNR^(a)R^(a) and    —NR^(a)(C₂₋₆)alkylOR^(a);-   R¹⁰ is H, (C₁₋₃)alkyl, (C₁₋₃)haloalkyl, cyano, nitro, CO₂R^(a),    C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    —S(═O)R^(b), S(═O)₂R^(b) or S(═O)₂NR^(a)R^(a); —R¹¹ is H or    (C₁₋₄)alkyl;-   R^(a) is independently, at each instance, H or R^(b); and-   R^(b) is independently, at each instance, phenyl, benzyl or    (C₁₋₆)alkyl, the phenyl, benzyl and (C₁₋₆)alkyl being substituted by    0, 1, 2 or 3 substituents selected from halo, (C₁₋₄)alkyl, (C₁₋₃)    haloalkyl, —O(C₁₋₄)alkyl, —NH₂, —NH(C₁₋₄)alkyl,    —N(C₁₋₄)alkyl(C₁₋₄)alkyl.

In another embodiment, the PI3K inhibitor (which may be a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is a compound ofFormula (VII):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, wherein:

-   X¹ is C(R⁹) or N;-   X² is C(R¹⁰) or N;-   Y is N(R¹¹), O or S;-   Z is CR⁸ or N;-   R¹ is a direct-bonded or oxygen-linked saturated,    partially-saturated or unsaturated 5-, 6- or 7-membered monocyclic    ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, but    containing no more than one O or S, wherein the available carbon    atoms of the ring are substituted by 0, 1 or 2 oxo or thioxo groups,    wherein the ring is substituted by 0 or 1 R² substituents, and the    ring is additionally substituted by 0, 1, 2 or 3 substituents    independently selected from halo, nitro, cyano, (C₁₋₄)alkyl,    O(C₁₋₄)alkyl, O(C₁₋₄)haloalkyl, NH(C₁₋₄)alkyl,    N(C₁₋₄)alkyl(C₁₋₄)alkyl and (C₁₋₄)haloalkyl;-   R² is selected from halo, (C₁₋₄)haloalkyl, cyano, nitro,    —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),    —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a),    —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆)alkylNR^(a)R^(a),    —OC₂₋₆)alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),    —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),    —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),    —N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)(C₂₋₆    alkylNR^(a)R^(a) and —NR^(a)(C₂₋₆)alkylOR^(a); or R² is selected    from (C₁₋₆)alkyl, phenyl, benzyl, heteroaryl, heterocycle, —(C₁₋₃    alkyl)heteroaryl, —(C₁₋₃ alkyl)heterocycle, —O(C₁₋₃    alkyl)heteroaryl, —O((C₁₋₃)alkyl)heterocycle, —NR^(a)(C₁₋₃    alkyl)heteroaryl, —NR^(a)(C₁₋₃ alkyl)heterocycle, —(C₁₋₃    alkyl)phenyl, —O(C₁₋₃ alkyl)phenyl and —NR^(a)(C₁₋₃ alkyl)phenyl all    of which are substituted by 0, 1, 2 or 3 substituents selected from    (C₁₋₄)haloalkyl, O(C₁₋₄)alkyl, Br, Cl, F, I and (C₁₋₄)alkyl;-   R³ is selected from H, halo, (C₁₋₄)haloalkyl, cyano, nitro,    —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),    —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a),    —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆)alkylNR^(a)R^(a),    —OC₂₋₆)alkylOR¹, —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),    —S(O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    —NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),    —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),    —N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),    —NR^(a)(C₂₋₆)alkylNR^(a)R^(a), —NR^(a)(C₂₋₆)alkylOR^(a),    (C₁₋₆)alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein the    (C₁₋₆)alkyl, phenyl, benzyl, heteroaryl and heterocycle are    additionally substituted by 0, 1, 2 or 3 substituents selected from    (C₁₋₆)haloalkyl, O(C₁₋₆)alkyl, Br, Cl, F, I and (C₁₋₆)alkyl;-   R⁵ is, independently, in each instance, H, halo, (C₁₋₆)alkyl,    (C₁₋₄)haloalkyl, or (C₁₋₆)alkyl substituted by 1, 2 or 3    substituents selected from halo, cyano, OH, O(C₁₋₄)alkyl,    (C₁₋₄)alkyl, (C₁₋₃)haloalkyl, O(C₁₋₄)alkyl, NH₂, NHC₁₋₄)alkyl,    N(C₁₋₄)alkyl(C₁₋₄)alkyl; or both R⁵ groups together form a    C₃₋₆-spiroalkyl substituted by 0, 1, 2 or 3 substituents selected    from halo, cyano, OH, O(C₁₋₄)alkyl, (C₁₋₄)alkyl, (C₁₋₃)haloalkyl,    O(C₁₋₄)alkyl, NH₂, NHC₁₋₄)alkyl, N(C₁₋₄)alkyl)C₁₋₄)alkyl;-   R⁶ is selected from H, halo, (C₁₋₆)alkyl, (C₁₋₄haloalkyl, cyano,    nitro, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),    —C(═NR^(a))NR^(a)R^(a), —S(═O)R^(a)S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a),    —S(═O)₂N(R^(a))C(═O)R^(a), —S(═O)₂N(R^(a))C(═O)OR^(a),    —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a);-   R⁷ is selected from H, halo, (C₁₋₆)alkyl, (C₁₋₄haloalkyl, cyano,    nitro, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),    —C(═NR^(a))NR^(a)R^(a), —S(═O)R^(a)S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a),    —S(═O)₂N(R^(a))C(═O)R^(a), —S(═O)₂N(R^(a))C(═O)OR^(a),    —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a);-   R⁸ is selected from H, (C₁₋₆)haloalkyl, Br, Cl, F, I, OR^(a),    NR^(a)R^(a), (C₁₋₆)alkyl, phenyl, benzyl, heteroaryl and    heterocycle, wherein the (C₁₋₆)alkyl, phenyl, benzyl, heteroaryl and    heterocycle are additionally substituted by 0, 1, 2 or 3    substituents selected from (C₁₋₆)haloalkyl, O(C₁₋₆)alkyl, Br, Cl, F,    I and (C₁₋₆)alkyl;-   R⁹ is selected from H, halo, (C₁₋₄)haloalkyl, cyano, nitro,    —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),    —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a),    —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆)alkylNR^(a)R^(a),    —OC₂₋₆)alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),    —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    —NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),    —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),    —N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),    —NR^(a)(C₂₋₆)alkylOR^(a), (C₁₋₆)alkyl, phenyl, benzyl, heteroaryl    and heterocycle, wherein the (C₁₋₆)alkyl, phenyl, benzyl, heteroaryl    and heterocycle are additionally substituted by 0, 1, 2 or 3    substituents selected from halo, (C₁₋₄)haloalkyl, cyano, nitro,    —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),    —C(═NR^(a))NR^(a)R^(a), —OR⁸, —OC(═O)R⁸, —OC(═O)NR²R⁸,    —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆)alkylNR^(a)R^(a),    —OC₂₋₆)alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R⁸,    —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    —NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),    —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),    —N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),    —NR^(a)(C₂₋₆)alkylNR^(a)R^(a), —NR^(a)(C₂₋₆)alkylOR^(a); or R⁹ is a    saturated, partially-saturated or unsaturated 5-, 6- or 7-membered    monocyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O    and S, but containing no more than one O or S, wherein the available    carbon atoms of the ring are substituted by 0, 1 or 2 oxo or thioxo    groups, wherein the ring is substituted by 0, 1, 2, 3 or 4    substituents selected from halo, (C₁₋₄)haloalkyl, cyano, nitro,    —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),    —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a),    —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆)alkylNR^(a)R^(a),    —OC₂₋₆)alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),    —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    —NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),    —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),    —N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),    —NR^(a)(C₂₋₆)alkylNR^(a)R^(a) and —NR^(a)(C₂₋₆)alkylOR^(a);-   R¹⁰ is H, (C₁₋₃ alkyl, (C₁₋₃)haloalkyl, cyano, nitro, CO₂R^(a),    C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    —S(═O)R^(b), S(═O)₂R^(b) or S(═O)₂NR^(a)R^(a);-   R¹¹ is H or (C₁₋₄)alkyl;-   R^(a) is independently, at each instance, H or R^(b); and-   R^(b) is independently, at each instance, phenyl, benzyl or    (C₁₋₆)alkyl, the phenyl, benzyl and (C₁₋₆)alkyl being substituted by    0, 1, 2 or 3 substituents selected from halo, (C₁₋₄)alkyl,    (C₁₋₃)haloalkyl, —O(C₁₋₄)alkyl, —NH₂, —NHC₁₋₄)alkyl,    —N(C₁₋₄)alkyl(C₁₋₄)alkyl.

In another embodiment, the PI3K inhibitor (which may be a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is a compound ofFormula (VIII):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, wherein:

-   X¹ is C(R⁹) or N;-   X² is C(R¹⁰) or N;-   Y is N(R¹¹), O or S;-   Z is CR⁸ or N;-   R¹ is a direct-bonded or oxygen-linked saturated,    partially-saturated or unsaturated 5-, 6- or 7-membered monocyclic    ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, but    containing no more than one O or S, wherein the available carbon    atoms of the ring are substituted by 0, 1 or 2 oxo or thioxo groups,    wherein the ring is substituted by 0 or 1 R² substituents, and the    ring is additionally substituted by 0, 1, 2 or 3 substituents    independently selected from halo, nitro, cyano, (C₁₋₄)alkyl,    O(C₁₋₄)alkyl, O(C₁₋₄)haloalkyl, NH(C₁₋₄)alkyl, N(C₁₋₄    alkyl)C₁₋₄)alkyl and (C₁₋₄)haloalkyl;-   R² is selected from halo, (C₁₋₄)haloalkyl, cyano, nitro,    —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a)—C(═NR^(a))NR^(a)R^(a),    —OR^(a), —OC(═O)R^(a), OC(═O)NR^(a)R^(a),    —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),    —S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    —NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),    —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),    —N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)(C₂₋₆    alkylNR^(a)R^(a) and —NR^(a)(C₂₋₆alkylOR^(a); or R² is selected from    (C₁₋₆alkyl, phenyl, benzyl, heteroaryl, heterocycle, —(C₁₋₃    alkyl)heteroaryl, —(C₁₋₃ alkyl)heterocycle, —O(C₁₋₃    alkyl)heteroaryl, —O(C₁₋₃ alkyl)heterocycle, —NR^(a)(C₁₋₃    alkyl)heteroaryl, —NR^(a)(C₁₋₃ alkyl)heterocycle, —(C₁₋₃    alkyl)phenyl, —O(C₁₋₃ alkyl)phenyl and —NR^(a)(C₁₋₃ alkyl)phenyl all    of which are substituted by 0, 1, 2 or 3 substituents selected from    (C₁₋₄ haloalkyl, O(C₁₋₄)alkyl, Br, Cl, F, I and (C₁₋₄)alkyl;-   R³ is selected from H, halo, (C₁₋₄)haloalkyl, cyano, nitro,    —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a)—C(═NR^(a))NR^(a)R^(a),    —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a),    —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),    —S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    —NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),    —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),    —N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)NR^(a), —NR^(a),    —NR^(a)(C₂₋₆)alkylOR^(a), (C₁₋₆)alkyl, phenyl, benzyl, heteroaryl    and heterocycle, wherein the (C₁₋₆)alkyl, phenyl, benzyl, heteroaryl    and heterocycle are additionally substituted by 0, 1, 2 or 3    substituents selected from (C₁₋₆)haloalkyl, O(C₁₋₆)alkyl, Br, Cl, F,    I and (C₁₋₆)alkyl;-   R⁵ is, independently, in each instance, H, halo, (C₁₋₆)alkyl,    (C₁₋₄)haloalkyl, or (C₁₋₆)alkyl substituted by 1, 2 or 3    substituents selected from halo, cyano, OH, O(C₁₋₄)alkyl,    (C₁₋₄)alkyl, (C₁₋₃)haloalkyl, O(C₁₋₄)alkyl, NH₂, NH(C₁₋₄)alkyl,    N(C₁₋₄)alkyl(C₁₋₄)alkyl; or both R⁵ groups together form a    C₃₋₆-spiroalkyl substituted by 0, 1, 2 or 3 substituents selected    from halo, cyano, OH, O(C₁₋₄)alkyl, (C₁₋₄)alkyl, (C₁₋₃)haloalkyl,    O(C₁₋₄)alkyl, NH₂, NH(C₁₋₄)alkyl, N(C₁₋₄)alkyl(C₁₋₄)alkyl;-   R⁶ is selected from H, halo, (C₁₋₆)alkyl, (C₁₋₄)haloalkyl, cyano,    nitro, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),    —C(═NR^(a))NR^(a)R^(a), —S(═O)R^(a), —S(═O)₂R^(a),    —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a);-   R⁷ is selected from H, halo, (C₁₋₆)alkyl, (C₁₋₄)haloalkyl, cyano,    nitro, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),    —C(═NR^(a))NR^(a)R^(a), —S(═O)R^(a), —S(═O)₂R^(a),    —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a);-   R⁸ is selected from H, (C₁₋₆)haloalkyl, Br, Cl, F, I, OR^(a),    NR^(a)R^(a), (C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle,    wherein the (C₁₋₆)alkyl, phenyl, benzyl, heteroaryl and heterocycle    are additionally substituted by 0, 1, 2 or 3 substituents selected    from (C₁₋₆)haloalkyl, OC₁₋₆ alkyl, Br, Cl, F, I and (C₁₋₆)alkyl;-   R⁹ is selected from H, halo, (C₁₋₄)haloalkyl, cyano, nitro,    —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),    —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a),    —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a),    —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),    —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    —NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),    —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),    —N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),    —NR^(a)(C₂₋₆alkylNR^(a)R^(a), —NR^(a)(C₂₋₆alkylOR^(a), (C₁₋₆)alkyl,    phenyl, benzyl, heteroaryl and heterocycle, wherein the (C₁₋₆)alkyl,    phenyl, benzyl, heteroaryl and heterocycle are additionally    substituted by 0, 1, 2 or 3 substituents selected from halo,    (C₁₋₄)haloalkyl, cyano, nitro, —C(═O)R^(a), —C(═O)OR^(a),    —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a),    —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylOR^(a),    —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a),    —S(═O)₂N(R^(a))C(═O)R^(a), —S(═O)₂N(R^(a))C(═O)OR^(a),    —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(a),    —N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)NR^(a)R^(a),    —N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(a),    —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)(C₂₋₆alkylNR^(a)R^(a),    —NR^(a)(C₂₋₆alkylOR^(a); or R⁹ is a saturated, partially-saturated    or unsaturated 5-, 6- or 7-membered monocyclic ring containing 0, 1,    2, 3 or 4 atoms selected from N, O and S, but containing no more    than one O or S, wherein the available carbon atoms of the ring are    substituted by 0, 1 or 2 oxo or thioxo groups, wherein the ring is    substituted by 0, 1, 2, 3 or 4 substituents selected from halo,    (C₁₋₄)haloalkyl, cyano, nitro, —C(O)R^(a), —C(═O)OR^(a),    —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a),    —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),    —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),    —S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    —NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),    —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),    —N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)(C₂₋₆    alkylNR^(a)R^(a) and —NR^(a)(C₂₋₆alkylOR^(a);-   R¹⁰ is H, (C₁₋₃ alkyl, (C₁₋₃)haloalkyl, cyano, nitro, CO₂R^(a),    C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),    —S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    —S(═O)R^(b), —S(═O)₂R^(b) or S(═O)₂NR^(a)R^(a);-   R¹¹ is H or (C₁₋₄)alkyl;-   R^(a) is independently, at each instance, H or R^(b); and-   R^(b) is independently, at each instance, phenyl, benzyl or    (C₁₋₆)alkyl, the phenyl, benzyl and (C₁₋₆) alkyl being substituted    by 0, 1, 2 or 3 substituents selected from halo, (C₁₋₄)alkyl, (C₁₋₃    haloalkyl, —O(C₁₋₄)alkyl, —NH₂, —NH(C₁₋₄)alkyl,    —N(C₁₋₄)alkyl(C₁₋₄)alkyl.

In a preferred embodiment, the PI3K inhibitor (which may be a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is a compound ofFormula (VIII) wherein X¹ is C(R⁹) and X² is N.

In a preferred embodiment, the PI3K inhibitor (which may be a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is a compound ofFormula (VIII) wherein X¹ is C(R⁹) and X² is C(R¹⁰).

In a preferred embodiment, the PI3K inhibitor (which may be a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is a compound ofFormula (VIII) wherein R¹ is phenyl substituted by 0, 1, 2, or 3independently selected R² substituents.

In a preferred embodiment, the PI3K inhibitor (which may be a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is a compound ofFormula (VIII) wherein R¹ is phenyl.

In a preferred embodiment, the PI3K inhibitor (which may be a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is a compound ofFormula (VIII) wherein R¹ is selected from 2-methylphenyl,2-chlorophenyl, 2-trifluoromethylphenyl, 2-fluorophenyl and2-methoxyphenyl.

In a preferred embodiment, the PI3K inhibitor (which may be a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is a compound ofFormula (VIII) wherein R¹ is phenoxy.

In a preferred embodiment, the PI3K inhibitor (which may be a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is a compound ofFormula (VIII) wherein R¹ is a direct-bonded or oxygen-linked saturated,partially-saturated or unsaturated 5-, 6- or 7-membered monocyclic ringcontaining 1, 2, 3 or 4 atoms selected from N, O and S, but containingno more than one O or S, wherein the available carbon atoms of the ringare substituted by 0, 1 or 2 oxo or thioxo groups, wherein the ring issubstituted by 0 or 1 R² substituents, and the ring is additionallysubstituted by 0, 1, 2 or 3 substituents independently selected fromhalo, nitro, cyano, C₁₋₄alkyl, OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl,N(C₁₋₄alkyl)C₁₋₄alkyl and C₁₋₄haloalkyl.

In a preferred embodiment, the PI3K inhibitor (which may be a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is a compound ofFormula (VIII) wherein R¹ is an unsaturated 5- or 6-membered monocyclicring containing 1, 2, 3 or 4 atoms selected from N, O and S, butcontaining no more than one O or S, wherein the ring is substituted by 0or 1 R² substituents, and the ring is additionally substituted by 0, 1,2 or 3 substituents independently selected from halo, nitro, cyano,C₁₋₄alkyl, OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl,N(C₁₋₄alkyl)C₁₋₄alkyl and C₁₋₄haloalkyl.

In a preferred embodiment, the PI3K inhibitor (which may be a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is a compound ofFormula (VIII) wherein R¹ is an unsaturated 5- or 6-membered monocyclicring containing 1, 2, 3 or 4 atoms selected from N, O and S, butcontaining no more than one O or S, wherein the ring is substituted by 0or 1 R² substituents, and the ring is additionally substituted by 1, 2or 3 substituents independently selected from halo, nitro, cyano,C₁₋₄alkyl, OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl,N(C₁₋₄alkyl)C₁₋₄alkyl and C₁₋₄ haloalkyl.

In a preferred embodiment, the PI3K inhibitor (which may be a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is a compound ofFormula (VIII) wherein R¹ is an unsaturated 5- or 6-membered monocyclicring containing 1, 2, 3 or 4 atoms selected from N, O and S.

In a preferred embodiment, the PI3K inhibitor (which may be a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is a compound ofFormula (VIII) wherein R¹ is selected from pyridyl and pyrimidinyl.

In a preferred embodiment, the PI3K inhibitor (which may be a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is a compound ofFormula (VIII) wherein R³ is selected from halo, C₁₋₄haloalkyl, cyano,nitro, —C(O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a),—SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(a), —S(═O)₂N(R^(a))C(O)OR^(a),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(a),—N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(a),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)(C₂₋₆alkylNR^(a)R^(a), —NR^(a),C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein theC₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle are additionallysubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₆)haloalkyl,OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl.

In a preferred embodiment, the PI3K inhibitor (which may be a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is a compound ofFormula (VIII) wherein R³ is H.

In a preferred embodiment, the PI3K inhibitor (which may be a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is a compound ofFormula (VIII) wherein R³ is selected from F, Cl, C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle, wherein the C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle are additionally substituted by 0, 1,2 or 3 substituents selected from C₁₋₆)haloalkyl, OC₁₋₆alkyl, Br, Cl, F,I and C₁₋₆alkyl.

In a preferred embodiment, the PI3K inhibitor (which may be a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is a compound ofFormula (VIII) wherein R⁵ is, independently, in each instance, H, halo,C₁₋₆alkyl, C₁₋₄haloalkyl, or C₁₋₆alkyl substituted by 1, 2 or 3substituents selected from halo, cyano, OH, OC₁₋₄)alkyl, C₁₋₄)alkyl,C₁₋₃)haloalkyl, OC₁₋₄)alkyl, NH₂, NHC₁₋₄)alkyl, N(C₁₋₄)alkyl)C₁₋₄)alkyl;or both R⁵ groups together form a C₃₋₆spiroalkyl substituted by 0, 1, 2or 3 substituents selected from halo, cyano, OH, OC₁₋₄)alkyl,C₁₋₄)alkyl, C₁₋₃)haloalkyl, OC₁₋₄)alkyl, NH₂, NHC₁₋₄)alkyl,N(C₁₋₄)alkyl)C₁₋₄)alkyl.

In a preferred embodiment, the PI3K inhibitor (which may be a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is a compound ofFormula (VIII) wherein R⁵ is H.

In a preferred embodiment, the PI3K inhibitor (which may be a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is a compound ofFormula (VIII) wherein one R⁵ is S-methyl, the other is H.

In a preferred embodiment, the PI3K inhibitor (which may be a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is a compound ofFormula (VIII) wherein at least one R⁵ is halo, C₁₋₆alkyl,C₁₋₄haloalkyl, or C₁₋₆alkyl substituted by 1, 2 or 3 substituentsselected from halo, cyano, OH, OC₁₋₄)alkyl, C₁₋₄)alkyl, C₁₋₃)haloalkyl,OC₁₋₄)alkyl, NH₂, NHC₁₋₄)alkyl, N(C₁₋₄)alkyl)C₁₋₄)alkyl.

In a preferred embodiment, the PI3K inhibitor (which may be a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is a compound ofFormula (VIII) wherein R⁶ is H.

In a preferred embodiment, the PI3K inhibitor (which may be a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is a compound ofFormula (VIII) wherein R⁶ is F, Cl, cyano or nitro.

In a preferred embodiment, the PI3K inhibitor (which may be a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is a compound ofFormula (VIII) wherein R⁷ is H.

In a preferred embodiment, the PI3K inhibitor (which may be a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is a compound ofFormula (VIII) wherein R⁷ is F, Cl, cyano or nitro.

In a preferred embodiment, the PI3K inhibitor (which may be a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is a compound ofFormula (VIII) wherein R⁸ is selected from H, CF₃, C₁₋₃ alkyl, Br, Cland F.

In a preferred embodiment, the PI3K inhibitor (which may be a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is a compound ofFormula (VIII) wherein R⁸ is selected from H.

In a preferred embodiment, the PI3K inhibitor (which may be a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is a compound ofFormula (VIII) wherein R⁸ is selected from CF₃, C₁₋₃ alkyl, Br, Cl andF.

In a preferred embodiment, the PI3K inhibitor (which may be a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is a compound ofFormula (VIII) wherein R⁹ is H.

In a preferred embodiment, the PI3K inhibitor (which may be a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is a compound ofFormula (VIII) wherein R⁹ is selected from halo, C₁₋₄haloalkyl, cyano,nitro, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a),—SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(a), —S(═O)₂N(R^(a))C(═O)OR^(a),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(a),—N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(a),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)(C₂₋₆alkylNR^(a)R^(a),—NR^(a)(C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl, benzyl, heteroaryl andheterocycle, wherein the C₁₋₆alkyl, phenyl, benzyl, heteroaryl andheterocycle are additionally substituted by 0, 1, 2 or 3 substituentsselected from halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)(C₂₋₆alkylNR^(a)R^(a), —NR^(a)(C₂₋₆alkylOR^(a).

In a preferred embodiment the PI3K inhibitor (which may be a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is a compound ofFormula (VIII) wherein R⁹ is a saturated, partially-saturated orunsaturated 5-, 6- or 7-membered monocyclic ring containing 0, 1, 2, 3or 4 atoms selected from N, O and S, but containing no more than one Oor S, wherein the available carbon atoms of the ring are substituted by0, 1 or 2 oxo or thioxo groups, wherein the ring is substituted by 0, 1,2, 3 or 4 substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)(C₂₋₆alkylNR^(a)R^(a) and —NR^(a)(C₂₋₆alkylOR^(a).

In a preferred embodiment, the PI3K inhibitor (which may be a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is a compound ofFormula (VIII) wherein R¹⁰ is H.

In a preferred embodiment, the PI3K inhibitor (which may be a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is a compound ofFormula (VIII) wherein R¹⁰ is cyano, nitro, CO₂R^(a), C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), S(═O)R^(b),S(═O)₂R^(b) or S(═O)₂NR^(a)R^(a).

In a preferred embodiment, the PI3K inhibitor (which may be a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is a compound ofFormula (VIII) wherein R¹¹ is H.

In a preferred embodiment, the PI3K-δ inhibitor is a compound of Formula(IX):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof.

In a preferred embodiment, the PI3K inhibitor or PI3K-δ inhibitor is(S)—N-(1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amineor a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof.

In a preferred embodiment, the PI3K-δ inhibitor is a compound of Formula(X):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof.

In a preferred embodiment, the PI3K inhibitor or PI3K-δ inhibitor is(S)—N-(1-(6-fluoro-3-(pyridin-2-yl)quinoxalin-2-yl)ethyl)-9H-purin-6-amineor a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof.

In a preferred embodiment, the PI3K-δ inhibitor is a compound of Formula(XI):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof.

In a preferred embodiment, the PI3K-δ inhibitor is(S)—N-(1-(2-(3,5-difluorophenyl)-8-fluoroquinolin-3-yl)ethyl)-9H-purin-6-amineor a pharmaceutically-acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof.

In a preferred embodiment, the PI3K-δ inhibitor is a compound of Formula(XII):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof.

In a preferred embodiment, the PI3K-δ inhibitor is(S)-3-(1-((9H-purin-6-yl)amino)ethyl)-2-(pyridin-2-yl)quinoline-8-carbonitrileor a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof.

In a preferred embodiment, the PI3K-δ inhibitor is a compound of Formula(XIII):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof

In a preferred embodiment, the PI3K-δ inhibitor is(S)—N-(1-(5,7-difluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amineor a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof.

In an embodiment, the PI3K inhibitor or PI3K-δ inhibitor is a compoundselected from the structures disclosed in U.S. Pat. Nos. 7,932,260 and8,207,153, the disclosure of which is incorporated by reference herein.In an embodiment, the PI3K inhibitor or PI3K-δ inhibitor is a compoundof Formula (XIV):

wherein

-   X and Y, independently, are N or CH;-   Z is N—R⁷ or O;-   R¹ are the same and are hydrogen, halo, or C₁₋₃ alkyl;-   R² and R³, independently, are hydrogen, halo, or C₁₋₃ alkyl;-   R⁴ is hydrogen, halo, OR^(a), CN, C₂₋₆alkynyl, C(═O)R^(a),    C(═O)NR^(a)R^(b), C₃₋₆heterocycloalkyl, C₁₋₃    alkyleneC₃₋₆heterocycloalkyl, O(C₁₋₃)alkyleneOR^(a),    O(C₁₋₃)alkyleneNR^(a)R^(b), O(C₁₋₃)alkyleneC₃₋₆ cycloalkyl,    OC₃₋₆heterocycloalkyl, O(C₁₋₃)alkyleneC≡CH, or    O(C₁₋₃)alkyleneC(═O)NR^(a)R^(b);-   R⁵ is (C₁₋₃)alkyl, CH₂CF₃, phenyl, CH₂C≡CH, (C₁₋₃)alkyleneOR^(e),    (C₁₋₄)alkyleneNR^(a)R^(b), or C₁₋₄ alkyleneNHC(═O)OR^(a),-   R⁶ is hydrogen, halo, or NR^(a)R^(b);-   R⁷ is hydrogen or R⁵ and R⁷ are taken together with the atoms to    which they are attached to form a five- or six-membered saturated    ring;-   R⁸ is C₁₋₃ alkyl, halo, CF₃, or CH₂C₃₋₆heterocycloalkyl;-   n is 0, 1, or 2;-   R^(a) is hydrogen, (C₁₋₄)alkyl, or CH₂C₆H₅;-   R^(b) is hydrogen or C₁₋₃ alkyl; and-   R^(c) is hydrogen, C₁₋₃ alkyl, or halo,-   wherein when the R¹ groups are different from hydrogen, R² and R⁴    are the same; or a pharmaceutically acceptable salt, solvate,    hydrate, cocrystal, or prodrug thereof.

In a preferred embodiment, the PI3K inhibitor or PI3K-δ inhibitor is anenantiomer of Formula (XIV), as shown in Formula (XV):

wherein X, Y, Z, R¹ through R⁸, R^(a), R^(b), R^(c), and n are asdefined above for Formula (XIV).

In various embodiments exhibiting increased potency relative to othercompounds, n=1, 2, or 3 and R⁸ is C₁₋₃alkyl, F, Cl, or CF₃.Alternatively, in such embodiments, n is 0 (such that there is no R⁸substituent).

In further embodiments exhibiting increased potency, X is N and Y is CH.Alternatively, X and Y may also both be CH.

In further embodiments exhibiting increased potency, R⁶ is hydrogen,halo, or NH₂. Preferably, R⁶ is hydrogen.

In preferred embodiments exhibiting increased potency, n is 0 or 1; R⁸(if n is 1) is C₁₋₃ alkyl, F, Cl, or CF₃; R⁶ is hydrogen; X is N and Yis CH or X and Y are both CH; Z is NH; R¹ are the same and are hydrogen,halo, or C₁₋₃alkyl; and R² and R³, independently, are hydrogen, halo, orC₁₋₃alkyl. Preferably, R¹, R², and R³ are hydrogen.

Unexpectedly, potency against PI3K-δ is conserved when R¹ is the same.In structural formulae (I) and (II), R² and R⁴ may differ provided thatR¹ is H. When R¹ is H, free rotation is unexpectedly permitted about thebond connecting the phenyl ring substituent to the quinazoline ring, andthe compounds advantageously do not exhibit atropisomerism (i.e.,multiple diasteromer formation is avoided). Alternatively, R² and R⁴ canbe the same such that the compounds advantageously do not exhibitatropisomerism.

In preferred embodiments, Z is N—R⁷, and the bicyclic ring systemcontaining X and Y is:

In other preferred embodiments of Formula (XIV) or Formula (XV), X, Y,Z, R^(a), R^(b), and R^(c) are as defined above for Formula (XIV), andR¹ is hydrogen, fluoro, chloro, methyl, or

and R² is hydrogen, methyl, chloro, or fluoro; R³ is hydrogen or fluoro;R⁶ is NH₂, hydrogen, or fluoro; R⁷ is hydrogen or R⁵ and R⁷ are takentogether to form

R⁸ is methyl, trifluoromethyl, chloro, or fluoro; R⁴ is hydrogen,fluoro, chloro, OH, OCH₃, OCH₂C≡CH, O(CH₂)₂N(CH₃)₂, C(═O)CH₃, C≡CH, CN,C(═O)NH₂, OCH₂C(═O)NH₂, O(CH₂)₂OCH₃, O(CH₂)₂N(CH₃)₂,

and R⁵ is methyl, ethyl, propyl, phenyl, CH₂OH, CH₂OCH₂C₆H₅, CH₂CF₃,CH₂OC(CH₃)₃, CH₂C≡CH, (CH₂)₃N(C₂H₅)₂, (CH₂)₃NH₂, (CH₂)₄NH₂,(CH₂)₃NHC(═O)OCH₂C₆H₅, or (CH₂)₄NHC(═O)OCH₂C₆H₅; R^(c) is hydrogen,methyl, fluoro, or bromo; and n is 0 or 1.

As used with respect to Formula (XIV) and Formula (XV), the term “alkyl”is defined as straight chained and branched hydrocarbon groupscontaining the indicated number of carbon atoms, e.g., methyl, ethyl,and straight chain and branched propyl and butyl groups. The terms“(C₁₋₃)alkylene” and “(C₁₋₄)alkylene” are defined as hydrocarbon groupscontaining the indicated number of carbon atoms and one less hydrogenthan the corresponding alkyl group. The term “(C₂₋₆)alkynyl” is definedas a hydrocarbon group containing the indicated number of carbon atomsand a carbon-carbon triple bond. The term “(C₃₋₆)cycloalkyl” is definedas a cyclic hydrocarbon group containing the indicated number of carbonatoms. The term “(C₂₋₆)heterocycloalkyl” is defined similarly ascycloalkyl except the ring contains one or two heteroatoms selected fromthe group consisting of O, NR^(a), and S. The term “halo” is defined asfluoro, bromo, chloro, and iodo.

In a preferred embodiment, the PI3K inhibitor (which may be a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is idelalisib. In apreferred embodiment, the PI3K inhibitor (which may be a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is the compound ofFormula (XVI):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof.

In a preferred embodiment, the PI3K inhibitor (which may be a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is(S)-2-(1-((9H-purin-6-yl)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-oneor a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof.

In an embodiment, the PI3K inhibitor (which may be a PI3K-γ inhibitor,PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is 4(3H)-quinazolinone,5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-5-fluoro-3-phenyl-2-{(1S)-1-[(7H-purin-6-yl)amino]propyl}quinazolin-4(3H)-oneor a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof

In an embodiment, the PI3K inhibitor (which may be a PI3K-γ inhibitor,PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) is GS-9901. Other PI3Kinhibitors suitable for use in the described combination with a BTKinhibitor also include, but are not limited to, those described in, forexample, U.S. Pat. No. 8,193,182 and U.S. Published Application Nos.2013/0267521; 2013/0053362; 2013/0029984; 2013/0029982; 2012/0184568;and 2012/0059000, the disclosures of each of which are incorporated byreference in their entireties.

BTK Inhibitors

The BTK inhibitor may be any BTK inhibitor known in the art. Inparticular, it is one of the BTK inhibitors described in more detail inthe following paragraphs.

In an embodiment, the BTK inhibitor is a compound of Formula (XVII):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, wherein:

-   X is CH, N, O or S;-   Y is C(R₆), N, O or S;-   Z is CH, N or bond;-   A is CH or N;-   B₁ is N or C(R₇);-   B₂ is N or C(R₈);-   B₃ is N or C(R₉);-   B₄ is N or C(R₁₀);-   R₁ is R₁₁C(═O), R₁₂S(═O), R₁₃S(═O)₂ or (C₁₋₆)alkyl optionally    substituted with R₁₄;-   R₂ is H, (C₁₋₃)alkyl or (C₃₋₇)cycloalkyl;-   R₃ is H, (C₁₋₆)alkyl or (C₃₋₇)cycloalkyl); or-   R₂ and R₃ form, together with the N and C atom they are attached to,    a (C₃₋₇)heterocycloalkyl optionally substituted with one or more    fluorine, hydroxyl, (C₁₋₃)alkyl, (C₁₋₃)alkoxy or oxo;-   R₄ is H or (C₁₋₃)alkyl;-   R₅ is H, halogen, cyano, (C₁₋₄)alkyl, (C₁₋₃)alkoxy,    (C₃₋₆)cycloalkyl, any alkyl group of which is optionally substituted    with one or more halogen; or R₅ is (C₆₋₁₀)aryl or    (C₂₋₆)heterocycloalkyl;-   R₆ is H or (C₁₋₃)alkyl; or-   R₅ and R₆ together may form a (C₃₋₇)cycloalkenyl or    (C₂₋₆)heterocycloalkenyl, each optionally substituted with    (C₁₋₃)alkyl or one or more halogens;-   R₇ is H, halogen, CF₃, (C₁₋₃)alkyl or (C₁₋₃)alkoxy;-   R₈ is H, halogen, CF₃, (C₁₋₃)alkyl or (C₁₋₃)alkoxy; or-   R₇ and R_(R) together with the carbon atoms they are attached to,    form (C₆₋₁₀)aryl or (C₁₋₉)heteroaryl;-   R₉ is H, halogen, (C₁₋₃)alkyl or (C₁₋₃)alkoxy;-   R₁₀ is H, halogen, (C₁₋₃)alkyl or (C₁₋₃)alkoxy;-   R₁₁ is independently selected from the group consisting of    (C₁₋₆)alkyl, (C₂₋₆)alkenyl and (C₂₋₆)alkynyl, where each alkyl,    alkenyl or alkynyl is optionally substituted with one or more    substituents selected from the group consisting of hydroxyl,    (C₁₋₄)alkyl, (C₃₋₇)cycloalkyl, [(C₁₋₄)alkyl]amino,    di[(C₁₋₄)alkyl]amino, (C₁₋₃)alkoxy, (C₃₋₇)cycloalkoxy, (C₆₋₁₀)aryl    and (C₃₋₇)heterocycloalkyl; or R₁₁ is    (C₁₋₃)alkyl-C(O)—S—(C₁₋₃)alkyl; or-   R₁₁ is (C₁₋₅)heteroaryl optionally substituted with one or more    substituents selected from the group consisting of halogen or cyano;-   R₁₂ and R₁₃ are independently selected from the group consisting of    (C₂₋₆)alkenyl or (C₂₋₆)alkynyl, both optionally substituted with one    or more substituents selected from the group consisting of hydroxyl,    (C₁₋₄)alkyl, (C₃₋₇)cycloalkyl, [(C₁₋₄)alkyl]amino,    di[(C₁₋₄)alkyl]amino, (C₁₋₃)alkoxy, (C₃₋₇)cycloalkoxy, (C₆₋₁₀)aryl    and (C₃₋₇)heterocycloalkyl; or a (C₁₋₅)heteroaryl optionally    substituted with one or more substituents selected from the group    consisting of halogen and cyano; and-   R₁₄ is independently selected from the group consisting of halogen,    cyano, (C₂₋₆)alkenyl and (C₂₋₆)alkynyl, both optionally substituted    with one or more substituents selected from the group consisting of    hydroxyl, (C₁₋₄)alkyl, (C₃₋₇)cycloalkyl, (C₁₋₄)alkylamino,    di[(C₁₋₄)alkyl]amino, (C₁₋₃)alkoxy, (C₃₋₇)cycloalkoxy, (C₆₋₁₀)aryl,    (C₁₋₅)heteroaryl and (C₃₋₇)heterocycloalkyl; with the proviso that:-   0 to 2 atoms of X, Y, Z can simultaneously be a heteroatom;-   when one atom selected from X, Y is O or S, then Z is a bond and the    other atom selected from X, Y can not be O or S;-   when Z is C or N then Y is C(R₆) or N and X is C or N;-   0 to 2 atoms of B₁, B₂, B₃ and B₄ are N;-   with the terms used having the following meanings:-   (C₁₋₂)alkyl means an alkyl group having 1 to 2 carbon atoms, being    methyl or ethyl,-   (C₁₋₃)alkyl means a branched or unbranched alkyl group having 1-3    carbon atoms, being methyl, ethyl, propyl or isopropyl;-   (C₁₋₄)alkyl means a branched or unbranched alkyl group having 1-4    carbon atoms, being methyl, ethyl, propyl, isopropyl, butyl,    isobutyl, sec-butyl and tert-butyl, (C₁₋₃)alkyl groups being    preferred;-   (C₁₋₅)alkyl means a branched or unbranched alkyl group having 1-5    carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl,    isobutyl, sec-butyl, tert-butyl, pentyl and isopentyl, (C₁₋₄)alkyl    groups being preferred. (C₁₋₆)Alkyl means a branched or unbranched    alkyl group having 1-6 carbon atoms, for example methyl, ethyl,    propyl, isopropyl, butyl, tert-butyl, n-pentyl and n-hexyl.    (C₁₋₅)alkyl groups are preferred, (C₁₋₄)alkyl being most preferred;-   (C₁₋₂)alkoxy means an alkoxy group having 1-2 carbon atoms, the    alkyl moiety having the same meaning as previously defined;-   (C₁₋₃)alkoxy means an alkoxy group having 1-3 carbon atoms, the    alkyl moiety having the same meaning as previously defined.    (C₁₋₂)alkoxy groups are preferred;-   (C₁₋₄)alkoxy means an alkoxy group having 1-4 carbon atoms, the    alkyl moiety having the same meaning as previously defined.    (C₁₋₃)alkoxy groups are preferred, (C₁₋₂)alkoxy groups being most    preferred;-   (C₂₋₄)alkenyl means a branched or unbranched alkenyl group having    2-4 carbon atoms, such as ethenyl, 2-propenyl, isobutenyl or    2-butenyl;-   (C₂₋₆)alkenyl means a branched or unbranched alkenyl group having    2-6 carbon atoms, such as ethenyl, 2-butenyl, and n-pentenyl,    (C₂₋₄)alkenyl groups being most preferred;-   (C₂₋₄)alkynyl means a branched or unbranched alkynyl group having    2-4 carbon atoms, such as ethynyl, 2-propynyl or 2-butynyl;-   (C₂₋₆)alkynyl means a branched or unbranched alkynyl group having    2-6 carbon atoms, such as ethynyl, propynyl, n-butynyl, n-pentynyl,    isopentynyl, isohexynyl or n-hexynyl. (C₂₋₄)alkynyl groups are    preferred; (C₃₋₆)cycloalkyl means a cycloalkyl group having 3-6    carbon atoms, being cyclopropyl, cyclobutyl, cyclopentyl or    cyclohexyl;-   (C₃₋₇)cycloalkyl means a cycloalkyl group having 3-7 carbon atoms,    being cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or    cycloheptyl;-   (C₂₋₆)heterocycloalkyl means a heterocycloalkyl group having 2-6    carbon atoms, preferably 3-5 carbon atoms, and one or two    heteroatoms selected from N, O and/or S, which may be attached via a    heteroatom if feasible, or a carbon atom; preferred heteroatoms are    N or O; also preferred are piperidine, morpholine, pyrrolidine and    piperazine; with the most preferred (C₂₋₆)heterocycloalkyl being    pyrrolidine; the heterocycloalkyl group may be attached via a    heteroatom if feasible;-   (C₃₋₇)heterocycloalkyl means a heterocycloalkyl group having 3-7    carbon atoms, preferably 3-5 carbon atoms, and one or two    heteroatoms selected from N, O and/or S. Preferred heteroatoms are N    or O; preferred (C₃₋₇) heterocycloalkyl groups are azetidinyl,    pyrrolidinyl, piperidinyl, homopiperidinyl or morpholinyl; more    preferred (C₃₋₇)heterocycloalkyl groups are piperidine, morpholine    and pyrrolidine; and the heterocycloalkyl group may be attached via    a heteroatom if feasible;-   (C₃₋₇)cycloalkoxy means a cycloalkyl group having 3-7 carbon atoms,    with the same meaning as previously defined, attached via a ring    carbon atom to an exocyclic oxygen atom;-   (C₆₋₁₀)aryl means an aromatic hydrocarbon group having 6-10 carbon    atoms, such as phenyl, naphthyl, tetrahydronaphthyl or indenyl; the    preferred (C₆₋₁₀)aryl group is phenyl;-   (C₁₋₅)heteroaryl means a substituted or unsubstituted aromatic group    having 1-5 carbon atoms and 1-4 heteroatoms selected from N, O    and/or S; the (C₁₋₅)heteroaryl may optionally be substituted;    preferred (C₁₋₅)heteroaryl groups are tetrazolyl, imidazolyl,    thiadiazolyl, pyridyl, pyrimidyl, triazinyl, thienyl or furyl, a    more preferred (C₁₋₅)heteroaryl is pyrimidyl;-   (C₁₋₉)heteroaryl means a substituted or unsubstituted aromatic group    having 1-9 carbon atoms and 1-4 heteroatoms selected from N, O    and/or S; the (C₁₋₉)heteroaryl may optionally be substituted;    preferred (C₁₋₉)heteroaryl groups are quinoline, isoquinoline and    indole;-   [(C₁₋₄)alkyl]amino means an amino group, monosubstituted with an    alkyl group containing 1-4 carbon atoms having the same meaning as    previously defined; preferred [(C₁₋₄)alkyl]amino group is    methylamino;-   di[(C₁₋₄)alkyl]amino means an amino group, disubstituted with alkyl    group(s), each containing 1-4 carbon atoms and having the same    meaning as previously defined; preferred di[(C₁₋₄)alkyl]amino group    is dimethylamino;-   halogen means fluorine, chlorine, bromine or iodine;-   (C₁₋₃)alkyl-C(O)—S—(C₁₋₃)alkyl means an alkyl-carbonyl-thio-alkyl    group, each of the alkyl groups having 1 to 3 carbon atoms with the    same meaning as previously defined;-   (C₃₋₇)cycloalkenyl means a cycloalkenyl group having 3-7 carbon    atoms, preferably 5-7 carbon atoms; preferred (C₃₋₇)cycloalkenyl    groups are cyclopentenyl or cyclohexenyl; cyclohexenyl groups are    most preferred;-   (C₂₋₆)heterocycloalkenyl means a heterocycloalkenyl group having 2-6    carbon atoms, preferably 3-5 carbon atoms; and 1 heteroatom selected    from N, O and/or S; preferred (C₂₋₆)heterocycloalkenyl groups are    oxycyclohexenyl and azacyclohexenyl group.-   In the above definitions with multifunctional groups, the attachment    point is at the last group.-   When, in the definition of a substituent, it is indicated that “all    of the alkyl groups” of said substituent are optionally substituted,    this also includes the alkyl moiety of an alkoxy group.-   A circle in a ring of Formula (XVII) indicates that the ring is    aromatic.-   Depending on the ring formed, the nitrogen, if present in X or Y,    may carry a hydrogen.

In a preferred embodiment, the BTK inhibitor is a compound of Formula(XVII) or a pharmaceutically acceptable salt thereof, wherein:

-   X is CH or S;-   Y is C(R₆);-   Z is CH or bond;-   A is CH;-   B₁ is N or C(R₇);-   B₂ is N or C(R₈);-   B₃ is N or CH;-   B₄ is N or CH;-   R₁ is R₁₁C(═O),-   R₂ is (C₁₋₃)alkyl;-   R₃ is (C₁₋₃)alkyl; or-   R₂ and R₃ form, together with the N and C atom they are attached to,    a (C₃₋₇)heterocycloalkyl ring selected from the group consisting of    azetidinyl, pyrrolidinyl, piperidinyl, and morpholinyl, optionally    substituted with one or more fluorine, hydroxyl, (C₁₋₃)alkyl, or    (C₁₋₃)alkoxy;-   R₄ is H;-   R₅ is H, halogen, cyano, (C₁₋₄)alkyl, (C₁₋₃)alkoxy,    (C₃₋₆)cycloalkyl, or an alkyl group which is optionally substituted    with one or more halogen;-   R₆ is H or (C₁₋₃)alkyl;-   R₇ is H, halogen or (C₁₋₃)alkoxy;-   R₈ is H or (C₁₋₃)alkyl; or-   R₇ and R₈ form, together with the carbon atom they are attached to a    (C₆₋₁₀)aryl or (C₁₋₉)heteroaryl;-   R₅ and R₆ together may form a (C₃₋₇)cycloalkenyl or    (C₂₋₆)heterocycloalkenyl, each optionally substituted with    (C₁₋₃)alkyl or one or more halogen;-   R₁₁ is independently selected from the group consisting of    (C₂₋₆)alkenyl and (C₂₋₆)alkynyl, where each alkenyl or alkynyl is    optionally substituted with one or more substituents selected from    the group consisting of hydroxyl, (C₁₋₄)alkyl, (C₃₋₇)cycloalkyl,    [(C₁₋₄)alkyl]amino, di[(C₁₋₄)alkyl]amino, (C₁₋₃)alkoxy,    (C₃₋₇)cycloalkoxy, (C₆₋₁₀)aryl and (C₃₋₇)heterocycloalkyl;-   with the proviso that 0 to 2 atoms of B₁, B₂, B₃ and B₄ are N.

In an embodiment of Formula (XVII), B₁ is C(R₇); B₂ is C(R₈); B₃ isC(R₉); B₄ is C(R₁₀); R₇, R₉, and R₁₀ are each H; and R₈ is hydrogen ormethyl.

In an embodiment of Formula (XVII), the ring containing X, Y and Z isselected from the group consisting of pyridyl, pyrimidyl, pyridazyl,triazinyl, thiazolyl, oxazolyl and isoxazolyl.

In an embodiment of Formula (XVII), the ring containing X, Y and Z isselected from the group consisting of pyridyl, pyrimidyl and pyridazyl.

In an embodiment of Formula (XVII), the ring containing X, Y and Z isselected from the group consisting of pyridyl and pyrimidyl.

In an embodiment of Formula (XVII), the ring containing X, Y and Z ispyridyl.

In an embodiment of Formula (XVII), R₅ is selected from the groupconsisting of hydrogen, fluorine, methyl, methoxy and trifluoromethyl.

In an embodiment of Formula (XVII), R₅ is hydrogen.

In an embodiment of Formula (XVII), R₂ and R₃ together form aheterocycloalkyl ring selected from the group consisting of azetidinyl,pyrrolidinyl, piperidinyl, homopiperidinyl and morpholinyl, optionallysubstituted with one or more of fluoro, hydroxyl, (C₁₋₃)alkyl and(C₁₋₃)alkoxy.

In an embodiment of Formula (XVII), R₂ and R₃ together form aheterocycloalkyl ring selected from the group consisting of azetidinyl,pyrrolidinyl and piperidinyl.

In an embodiment of Formula (XVII), R₂ and R₃ together form apyrrolidinyl ring.

In an embodiment of Formula (XVII), R₁ is independently selected fromthe group consisting of (C₁₋₆)alkyl, (C₂₋₆)alkenyl or (C₂₋₆)alkynyl,each optionally substituted with one or more substituents selected fromthe group consisting of hydroxyl, (C₁₋₄)alkyl, (C₃₋₇)cycloalkyl,[(C₁₋₄)alkyl]amino, di[(C₁₋₄)alkyl] amino, (C₁₋₃)alkoxy,(C₃₋₇)cycloalkoxy, (C₆₋₁₀)aryl and (C₃₋₇)heterocycloalkyl.

In an embodiment of Formula (XVII), B₁, B₂, B₃ and B₄ are CH; X is N; Yand Z are CH; R₅ is CH₃; A is N; R₂, R₃ and R₄ are H; and R₁ is CO—CH₃.

In an embodiment of Formula (XVII), B₁, B₂, B₃ and B₄ are CH; X and Yare N; Z is CH; R₅ is CH₃; A is N; R₂, R₃ and R₄ are H; and R₁ isCO—CH₃.

In an embodiment of Formula (XVII), B₁, B₂, B₃ and B₄ are CH; X and Yare N; Z is CH; R₅ is CH₃; A is CH; R₂ and R₃ together form apiperidinyl ring; R₄ is H; and R₁ is CO-ethenyl.

In an embodiment of Formula (XVII), B₁, B₂, B₃ and B₄ are CH; X, Y and Zare CH; R₅ is H; A is CH; R₂ and R₃ together form a pyrrolidinyl ring;R₄ is H; and R₁ is CO-propynyl.

In an embodiment of Formula (XVII), B₁, B₂, B₃ and B₄ are CH; X, Y and Zare CH; R₅ is CH₃; A is CH; R₂ and R₃ together form a piperidinyl ring;R₄ is H; and R₁ is CO-propynyl.

In an embodiment of Formula (XVII), B₁, B₂, B₃ and B₄ are CH; X and Yare N; Z is CH; R₅ is H; A is CH; R₂ and R₃ together form a morpholinylring; R₄ is H; and R₁ is CO-ethenyl.

In an embodiment of Formula (XVII), B₁, B₂, B₃ and B₄ are CH; X and Yare N; Z is CH; R₅ is CH₃; A is CH; R₂ and R₃ together form amorpholinyl ring; R₄ is H; and R₁ is CO-propynyl.

In a preferred embodiment, the BTK inhibitor is a compound of Formula(XVIII):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. The preparation of this compound is described inInternational Patent Application Publication No. WO 2013/010868, thedisclosure of which is incorporated herein by reference.

In a preferred embodiment, the BTK inhibitor is(S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamideor pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug therof.

In a preferred embodiment, the BTK inhibitor is a compound of Formula(XVIII-A):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. The preparation of this compound is described inInternational Patent Application Publication No. WO 2013/010868, thedisclosure of which is incorporated herein by reference.

In a preferred embodiment, the BTK inhibitor is a compound of Formula(XVIII-B):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. The preparation of this compound is described inInternational Patent Application Publication No. WO 2013/010868, thedisclosure of which is incorporated herein by reference.

In a preferred embodiment, the BTK inhibitor is a compound of Formula(XVIII-C):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. The preparation of this compound is described inInternational Patent Application Publication No. WO 2013/010868, thedisclosure of which is incorporated herein by reference.

In a preferred embodiment, the BTK inhibitor is a compound of Formula(XVIII-D):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. The preparation of this compound is described inInternational Patent Application Publication No. WO 2013/010868, thedisclosure of which is incorporated herein by reference.

In a preferred embodiment, the BTK inhibitor is a compound of Formula(XVIII-E):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. The preparation of this compound is described inInternational Patent Application Publication No. WO 2013/010868, thedisclosure of which is incorporated herein by reference.

In other embodiments, the BTK inhibitors include, but are not limitedto, those compounds described in International Patent ApplicationPublication No. WO 2013/010868, the disclosures of each of which arespecifically incorporated by reference herein.

In an embodiment, the BTK inhibitor is a compound of Formula (XIX) or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug of a compound of Formula (XIX):

In Formula (XIX) the substituents are defined as

-   X is CH, N, O or S;-   Y is C(R₆), N, O or S;-   Z is CH, N or bond;-   A is CH or N;-   B₁ is N or C(R₇);-   B₂ is N or C(R₈);-   B₃ is N or C(R₉);-   B₄ is N or C(R₁₀);-   R₁ is R₁₁C(O), R₁₂S(O), R₁₃SO₂ or (C₁₋₆)alkyl optionally substituted    with R₁₄;-   R₂ is H, (C₁₋₃)alkyl or (C₃₋₇)cycloalkyl;-   R₃ is H, (C₁₋₆)alkyl or (C₃₋₇)cycloalkyl); or-   R₂ and R₃ form, together with the N and C atom they are attached to,    a (C₃₋₇)heterocycloalkyl optionally substituted with one or more    fluorine, hydroxyl, (C₁₋₃)alkyl, (C₁₋₃)alkoxy or oxo;-   R₄ is H or (C₁₋₃)alkyl;-   R₅ is H, halogen, cyano, (C₁₋₄)alkyl, (C₁₋₃)alkoxy,    (C₃₋₆)cycloalkyl; all alkyl groups of R5 are optionally substituted    with one or more halogen; or R₅ is (C₆₋₁₀)aryl or    (C₂₋₆)heterocycloalkyl;-   R₆ is H or (C₁₋₃)alkyl; or R₅ and R₆ together may form a    (C₃₋₇)cycloalkenyl, or (C₂₋₆)heterocycloalkenyl; each optionally    substituted with (C₁₋₃)alkyl, or one or more halogen;-   R₇ is H, halogen, CF₃, (C₁₋₃)alkyl or (C₁₋₃)alkoxy;-   R₈ is H, halogen, CF₃, (C₁₋₃)alkyl or (C₁₋₃)alkoxy; or-   R₇ and R₈ together with the carbon atoms they are attached to, form    (C₆₋₁₀)aryl or (C₁₋₅)heteroaryl;-   R₉ is H, halogen, (C₁₋₃)alkyl or (C₁₋₃)alkoxy;-   R₁₀ is H, halogen, (C₁₋₃)alkyl or (C₁₋₃)alkoxy;-   R₁₁ is independently selected from a group consisting of    (C₁₋₆)alkyl, (C₂₋₆)alkenyl and (C₂₋₆)alkynyl each alkyl, alkenyl or    alkynyl optionally substituted with one or more groups selected from    hydroxyl, (C₁₋₄)alkyl, (C₃₋₇)cycloalkyl, [(C₁₋₄)alkyl]amino,    di[(C₁₋₄)alkyl]amino, (C₁₋₃)alkoxy, (C₃₋₇)cycloalkoxy, (C₆₋₁₀)aryl    or (C₃₋₇)heterocycloalkyl, or-   R₁₁ is (C₁₋₃)alkyl-C(O)—S—(C₁₋₃)alkyl; or-   R₁₁ is (C₁₋₅)heteroaryl optionally substituted with one or more    groups selected from halogen or cyano.-   R₁₂ and R₁₃ are independently selected from a group consisting of    (C₂₋₆)alkenyl or (C₂₋₆)alkynyl both optionally substituted with one    or more groups selected from hydroxyl, (C₁₋₄)alkyl,    (C₃₋₇)cycloalkyl, [(C₁₋₄)alkyl]amino, di[(C₁₋₄)alkyl]amino,    (C₁₋₃)alkoxy, (C₃₋₇)cycloalkoxy, (C₆₋₁₀)aryl, or    (C₃₋₇)heterocycloalkyl; or-   (C₁₋₅)heteroaryl optionally substituted with one or more groups    selected from halogen or cyano;-   R₁₄ is independently selected from a group consisting of halogen,    cyano or (C₂₋₆)alkenyl or (C₂₋₆)alkynyl both optionally substituted    with one or more groups selected from hydroxyl, (C₁₋₄)alkyl,    (C₃₋₇)cycloalkyl, [(C₁₋₄)alkyl]amino, di[(C₁₋₄)alkyl]amino,    (C₁₋₃)alkoxy, (C₃₋₇)cycloalkoxy, (C₆₋₁₀)aryl, (C₁₋₅)heteroaryl or    (C₃₋₇)heterocycloalkyl;-   with the proviso that    -   0 to 2 atoms of X, Y, Z can simultaneously be a heteroatom;    -   when one atom selected from X, Y is O or S, then Z is a bond and        the other atom selected from X, Y can not be O or S;    -   when Z is C or N then Y is C(R₆) or N and X is C or N;    -   0 to 2 atoms of B₁, B₂, B₃ and B₄ are N;-   with the terms used having the following meanings:-   (C₁₋₃)alkyl means a branched or unbranched alkyl group having 1-3    carbon atoms, being methyl, ethyl, propyl or isopropyl;-   (C₁₋₄)alkyl means a branched or unbranched alkyl group having 1-4    carbon atoms, being methyl, ethyl, propyl, isopropyl, butyl,    isobutyl, sec-butyl and tert-butyl, (C₁₋₃)alkyl groups being    preferred;-   (C₁₋₆)alkyl means a branched or unbranched alkyl group having 1-6    carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl,    tert-butyl, n-pentyl and n-hexyl. (C₁₋₅)alkyl groups are preferred,    (C₁₋₄)alkyl being most preferred;-   (C₁₋₂)alkoxy means an alkoxy group having 1-2 carbon atoms, the    alkyl moiety having the same meaning as previously defined;-   (C₁₋₃)alkoxy means an alkoxy group having 1-3 carbon atoms, the    alkyl moiety having the same meaning as previously defined, with    (C₁₋₂)alkoxy groups preferred;-   (C₂₋₃)alkenyl means an alkenyl group having 2-3 carbon atoms, such    as ethenyl or 2-propenyl;-   (C₂₋₄)alkenyl means a branched or unbranched alkenyl group having    2-4 carbon atoms, such as ethenyl, 2-propenyl, isobutenyl or    2-butenyl;-   (C₂₋₆)alkenyl means a branched or unbranched alkenyl group having    2-6 carbon atoms, such as ethenyl, 2-butenyl, and n-pentenyl, with    (C₂₋₄)alkenyl groups preferred, and (C₂₋₃)alkenyl groups even more    preferred;-   (C₂₋₄)alkynyl means a branched or unbranched alkynyl group having    2-4 carbon atoms, such as ethynyl, 2-propynyl or 2-butynyl;-   (C₂₋₃)alkynyl means an alkynyl group having 2-3 carbon atoms, such    as ethynyl or 2-propynyl;-   (C₂₋₆)alkynyl means a branched or unbranched alkynyl group having    2-6 carbon atoms, such as ethynyl, propynyl, n-butynyl, n-pentynyl,    isopentynyl, isohexynyl or n-hexynyl, with (C₂₋₄)alkynyl groups    preferred, and (C₂₋₃)alkynyl groups more preferred;-   (C₃₋₆)cycloalkyl means a cycloalkyl group having 3-6 carbon atoms,    being cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;-   (C₃₋₇)cycloalkyl means a cycloalkyl group having 3-7 carbon atoms,    being cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or    cycloheptyl;-   (C₂₋₆)heterocycloalkyl means a heterocycloalkyl group having 2-6    carbon atoms, preferably 3-5 carbon atoms, and one or two    heteroatoms selected from N, O and/or S, which may be attached via a    heteroatom if feasible, or a carbon atom; preferred heteroatoms are    N or O; preferred groups are piperidine, morpholine, pyrrolidine and    piperazine; a most preferred (C₂₋₆)heterocycloalkyl is pyrrolidine;    and the heterocycloalkyl group may be attached via a heteroatom if    feasible;-   (C₃₋₇)heterocycloalkyl means a heterocycloalkyl group having 3-7    carbon atoms, preferably 3-5 carbon atoms, and one or two    heteroatoms selected from N, O and/or S; preferred heteroatoms are N    or O; preferred (C₃₋₇) heterocycloalkyl groups are azetidinyl,    pyrrolidinyl, piperidinyl, homopiperidinyl or morpholinyl; more    preferred (C₃₋₇)heterocycloalkyl groups are piperidine, morpholine    and pyrrolidine; even more preferred are piperidine and pyrrolodine;    and the heterocycloalkyl group may be attached via a heteroatom if    feasible;-   (C₃₋₇)cycloalkoxy means a cycloalkyl group having 3-7 carbon atoms,    with the same meaning as previously defined, attached via a ring    carbon atom to an exocyclic oxygen atom;-   (C₆₋₁₀)aryl means an aromatic hydrocarbon group having 6-10 carbon    atoms, such as phenyl, naphthyl, tetrahydronaphthyl or indenyl; the    preferred (C₆₋₁₀)aryl group is phenyl;-   (C₁₋₅)heteroaryl means a substituted or unsubstituted aromatic group    having 1-5 carbon atoms and 1-4 heteroatoms selected from N, O    and/or S, wherein the (C₁₋₅)heteroaryl may optionally be    substituted; preferred (C₁₋₅)heteroaryl groups are tetrazolyl,    imidazolyl, thiadiazolyl, pyridyl, pyrimidyl, triazinyl, thienyl or    furyl, and the more preferred (C₁₋₅)heteroaryl is pyrimidyl;-   [(C₁₋₄)alkyl]amino means an amino group, monosubstituted with an    alkyl group containing 1-4 carbon atoms having the same meaning as    previously defined; the preferred [(C₁₋₄)alkyl]amino group is    methylamino;-   di[(C₁₋₄)alkyl]amino means an amino group, disubstituted with alkyl    group(s), each containing 1-4 carbon atoms and having the same    meaning as previously defined; the preferred di[(C₁₋₄)alkyl]amino    group is dimethylamino;-   halogen means fluorine, chlorine, bromine or iodine;-   (C₁₋₃)alkyl-C(O)—S—(C₁₋₃)alkyl means an alkyl-carbonyl-thio-alkyl    group, each of the alkyl groups having 1 to 3 carbon atoms with the    same meaning as previously defined;-   (C₃₋₇)cycloalkenyl means a cycloalkenyl group having 3-7 carbon    atoms, preferably 5-7 carbon atoms; preferred (C₃₋₇)cycloalkenyl    groups are cyclopentenyl or cyclohexenyl; and cyclohexenyl groups    are most preferred;-   (C₂₋₆)heterocycloalkenyl means a heterocycloalkenyl group having 2-6    carbon atoms, preferably 3-5 carbon atoms; and 1 heteroatom selected    from N, O and/or S; the preferred (C₂₋₆)heterocycloalkenyl groups    are oxycyclohexenyl and azacyclohexenyl groups.-   In the above definitions with multifunctional groups, the attachment    point is at the last group.-   When, in the definition of a substituent, is indicated that “all of    the alkyl groups” of said substituent are optionally substituted,    this also includes the alkyl moiety of an alkoxy group.-   A circle in a ring of Formula (XIX) indicates that the ring is    aromatic.-   Depending on the ring formed, the nitrogen, if present in X or Y,    may carry a hydrogen.

In a preferred embodiment, the invention relates to a compound accordingto Formula (XIX) wherein B₁ is C(R₇); B₂ is C(R₈); B₃ is C(R₉) and B₄ isC(R₁₀).

In other embodiments, the BTK inhibitors include, but are not limitedto, those compounds described in International Patent ApplicationPublication No. WO 2013/010869, the disclosures of each of which arespecifically incorporated by reference herein.

In an embodiment, the BTK inhibitor is a compound of Formula (XX):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, wherein:

-   L_(a) is CH₂, O, NH or S;-   Ar is a substituted or unsubstituted aryl, or a substituted or    unsubstituted heteroaryl;-   Y is an optionally substituted group selected from the group    consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl    and heteroaryl;-   Z is C(═O), OC(═O), NRC(═O), C(═S), S(═O)_(x), OS(═O)_(x) or    NRS(═O)_(x), where x is 1 or 2;-   R⁷ and R⁸ are each independently H; or R⁷ and R⁸ taken together form    a bond;-   R⁶ is H; and-   R is H or (C₁₋₆)alkyl.

In an embodiment, the BTK inhibitor is ibrutinib or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. In anexemplary embodiment, the BTK inhibitor is(R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one.In an exemplary embodiment, the BTK inhibitor is1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one.In an exemplary embodiment, the BTK inhibitor is(S)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one.In an exemplary embodiment, the BTK inhibitor has the structure ofFormula (XX-A), or an enantiomer thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.

In an exemplary embodiment, the BTK inhibitor is a compound of Formula(XXI):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, wherein:

-   L_(a) is CH₂, O, NH or S;-   Ar is a substituted or unsubstituted aryl, or a substituted or    unsubstituted heteroaryl;-   Y is an optionally substituted group selected from the group    consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl    and heteroaryl;-   Z is C(═O), OC(═O), NRC(═O), C(═S), S(═O)_(x), OS(═O)_(x) or    NRS(═O)_(x), where x is 1 or 2;-   R⁷ and R⁸ are each H; or R⁷ and R⁸ taken together form a bond;-   R⁶ is H, and-   R is H or (C₁₋₆)alkyl.

In an embodiment, the BTK inhibitor is a compound of Formula (XXII):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, wherein:

-   L_(a) is CH₂, O, NH or S;-   Ar is a substituted or unsubstituted aryl, or a substituted or    unsubstituted heteroaryl;-   Y is an optionally substituted group selected from the group    consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl    and heteroaryl;-   Z is C(═O), OC(═O), NRC(═O), C(═S), S(═O)_(x), OS(═O)_(x) or    NRS(═O)_(x), where x is 1 or 2;-   R⁷ and R⁸ are each H; or R⁷ and R⁸ taken together form a bond;-   R⁶ is H; and-   R is H or (C₁₋₆)alkyl.

In an embodiment, the BTK inhibitor is a compound of Formula (XXIII):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, wherein:

-   L_(a) is CH₂, O, NH or S;-   Ar is a substituted or unsubstituted aryl, or a substituted or    unsubstituted heteroaryl;-   Y is an optionally substituted group selected from the group    consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl    and heteroaryl;-   Z is C(═O), OC(═O), NRC(═O), C(═S), S(═O)_(x), OS(═O)_(x) or    NRS(═O)_(x), where x is 1 or 2;-   R⁷ and R⁸ are each H; or R⁷ and R⁸ taken together form a bond;-   R⁶ is H; and-   R is H or (C₁₋₆)alkyl.

In an embodiment, the BTK inhibitor is a compound disclosed in U.S. Pat.No. 7,459,554, the disclosure of which is specifically incorporatedherein by reference. In an embodiment, the BTK inhibitor is a compoundof Formula (XXIV):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, wherein:

-   Q¹ is aryl¹, heteroaryl¹, cycloalkyl, heterocyclyl, cycloalkenyl, or    heterocycloalkenyl, any of which is optionally substituted by one to    five independent G¹ substituents;-   R¹ is alkyl, cycloalkyl, bicycloalkyl, aryl, heteroaryl, aralkyl,    heteroaralkyl, heterocyclyl, or heterobicycloalkyl, any of which is    optionally substituted by one or more independent G¹¹ substituents;-   G¹ and G⁴¹ are each independently halo, oxo, —CF₃, —OCF₃, —OR²,    —NR²R³(R^(3a))_(j1), —C(O)R², —CO₂R², —CONR²R³, —NO₂, —CN,    —S(O)_(j1)R², —SO₂NR²R³, NR²(C═O)R³, NR²(C═O)OR³, NR²(C═O)NR²R³,    NR²S(O)_(j1)R³, —(C═S)OR², —(C═O)SR², —NR²(C═NR³)NR^(2a)R^(3a),    —NR²(C═NR³)OR^(2a), —NR²(C═NR³)SR^(3a), —O(C═O)OR², —O(C═O)NR²R³,    —O(C═O)SR², —S(C═O)OR², —S(C═O)NR²R³, (C₀₋₁₀)alkyl, (C₂₋₁₀)alkenyl,    (C₂₋₁₀)alkynyl, (C₁₋₁₀)alkoxy(C₁₋₁₀)alkyl,    (C₁₋₁₀)alkoxy(C₂₋₁₀)alkenyl, (C₁₋₁₀)alkoxy(C₂₋₁₀)alkynyl,    (C₁₋₁₀)alkylthio(C₁₋₁₀) alkyl, (C₁₋₁₀)alkylthio(C₂₋₁₀)alkenyl,    (C₁₋₁₀)alkylthio(C₂₋₁₀)alkynyl, cyclo(C₃₋₈)alkyl,    cyclo(C₃₋₈)alkenyl, cyclo(C₃₋₈)alkyl(C₁₋₁₀)alkyl,    cyclo(C₃₋₈)alkenyl(C₁₋₁₀)alkyl, cyclo(C₃₋₈) alkyl(C₂₋₁₀)alkenyl,    cyclo(C₃₋₈)alkenyl(C₂₋₁₀)alkenyl, cyclo(C₃₋₈)alkyl(C₂₋₁₀)alkynyl,    cyclo(C₃₋₈)alkenyl(C₂₋₁₀)alkynyl, heterocyclyl-(C₀₋₁₀)alkyl,    heterocyclyl-(C₂₋₁₀)alkenyl, or heterocyclyl-(C₂₋₁₀)alkynyl, any of    which is optionally substituted with one or more independent halo,    oxo, —CF₃, —OCF₃, —OR²²², —NR²²²R³³³(R³³³a)_(j1a), —C(O)R²²²,    —CO₂R²²², —CONR²²²R³³³, —NO₂, —CN, —S(O)_(j1a)R²²², —SO₂NR²²²R³³³,    NR²²²(C═O)R³³³, NR²²²(C═O)OR³³³, NR²²²(C═O)NR²²²R³³³,    NR²²²S(O)_(j1a)R³³³, —(C═S)OR²²², —(C═O)SR²²²,    —NR²²²(C═NR³³³)NR^(222a)R^(333a), —NR²²²(C═NR³³³)OR^(222a),    —NR²²²(C═NR³³³)SR^(333a), —O(C═O)OR²²², —O(C═O)NR²²²R³³³,    —O(C═O)SR²²², —S(C═O)OR²²², or —S(C═O)NR²²²R³³³ substituents; or    —(X¹)_(n)—(Y¹)_(m)—R⁴; or aryl-(C₀₋₁₀)alkyl, aryl-(C₂₋₁₀)alkenyl, or    aryl-(C₂₋₁₀) alkynyl, any of which is optionally substituted with    one or more independent halo, —CF₃, —OCF₃, —OR²²²,    —NR²²²R³³³(R^(333a))_(j2a), —C(O)R²²², —CO₂R²²², —CONR²²²R³³³, —NO₂,    —CN, —S(O)_(j2a)R²²², —SO₂NR²²²R³³³, NR²²²(C═O)R³³³,    NR²²²(C═O)OR³³³, NR²²²(C═O)NR²²²R³³³, NR²²²S(O)_(j2a)R³³³,    —(C═S)OR²²², —(C═O)SR²²², —NR²²²(C═NR³³³)NR^(222a)R^(333a),    —NR²²²(C═NR³³³)OR^(222a), —NR²²²(C═NR³³³)SR^(333a), —O(C═O)OR²²²,    —O(C═O)NR²²²R³³³, —O(C═O)SR²²², —S(C═O)OR²²², or —S(C═O)NR²²²R³³³    substituents; or hetaryl-(C₀₋₁₀)alkyl, hetaryl-(C₂₋₁₀)alkenyl, or    hetaryl-(C₂₋₁₀)alkynyl, any of which is optionally substituted with    one or more independent halo, —CF₃, —OCF₃, —OR²²², —NR²²²,    R³³³(R^(333a))_(j3a), —C(O)R²²², —CO₂R²²², —CONR²²²R³³³, —NO₂, —CN,    —S(O)_(j3a)R²²², —SO₂NR²²²R³³³, NR²²²(C═O)R³³³, NR²²²(C═O)OR³³³,    NR²²²(C═O)NR²²²R³³³, NR²²²S(O)_(j3a)R³³³, —(C═S)OR²²², —(C═O)SR²²²,    —NR²²²(C═NR³³³)N²²²aR³³³a, —NR²²²(C═NR³³³)OR^(222a),    —NR²²²(C═NR³³³)SR³³³a, —O(C═O)OR²²², —O(C═O)NR²²²R³³³, —O(C═O)SR²²²,    —S(C═O)OR²²², or —S(C═O)NR²²²R³³³ substituents;-   G¹¹ is halo, oxo, —CF₃, —OCF₃, —OR²¹, —NR²¹R³¹(R^(3a1))_(j4),    —C(O)R²¹, —CO₂R²¹, —CONR²¹R³¹, —NO₂, —CN, —S(O)_(j4)R²¹,    —SO₂NR²¹R³¹, NR²¹(C═O)R³¹, NR²¹(C═O)OR³¹, N²¹(C═O)NR²¹R³¹,    NR²¹S(O)_(j4)R³¹, —(C═S)OR²¹, —(C═O)SR²¹,    —NR²¹(C═NR³¹)NR^(2a1)R^(3a1), —NR²¹(C═NR³¹)OR^(2a1),    —NR²¹(C═NR³¹)SR^(3a1), —O(C═O)OR²¹, —O(C═O)NR²¹R³¹, —O(C═O)SR²¹,    —S(C═O)OR²¹, —S(C═O)NR²¹R³¹, —P(O)OR²¹OR³¹, (C₀₋₁₀)alkyl,    (C₂₋₁₀)alkenyl, (C₂₋₁₀)alkynyl, (C₁₋₁₀) alkoxy(C₁₋₁₀)alkyl,    (C₁₋₁₀)alkoxy(C₂₋₁₀)alkenyl, (C₁₋₁₀)alkoxy(C₂₋₁₀)alkynyl, (C₁₋₁₀)    alkylthio(C₁₋₁₀)alkyl, (C₁₋₁₀)alkylthio(C₂₋₁₀)alkenyl,    (C₁₋₁₀)alkylthio(C₂₋₁₀)alkynyl, cyclo(C₃₋₈)alkyl,    cyclo(C₃₋₈)alkenyl, cyclo(C₃₋₈)alkyl(C₁₋₁₀)alkyl,    cyclo(C₃₋₈)alkenyl(C₁₋₁₀) alkyl, cyclo(C₃₋₈)alkyl(C₂₋₁₀)alkenyl,    cyclo(C₃₋₈)alkenyl(C₂₋₁₀)alkenyl, cyclo(C₃₋₈) alkyl(C₂₋₁₀) alkynyl,    cyclo(C₃₋₈)alkenyl(C₂₋₁₀)alkynyl, heterocyclyl-(C₀₋₁₀)alkyl,    heterocyclyl-(C₂₋₁₀) alkenyl, or heterocyclyl-(C₂₋₁₀)alkynyl, any of    which is optionally substituted with one or more independent halo,    oxo, —CF₃, —OCF₃, —OR²²²¹, —N²²²¹R³³³¹(R^(333a1))_(j4a), —C(O)R²²²¹,    —CO₂R²²²¹, —CONR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j4a)R²²²¹,    —SO₂NR²²²¹R³³³¹, NR²²²¹(C═O)R³³³¹, NR²²²¹(C═O)OR³³³¹,    NR²²²¹(C═O)NR²²²¹R³³³¹, NR²²²¹S(O)_(j4a)R³³³¹, —(C═S)OR²²²¹,    —(C═O)SR²²²¹, —NR²²²¹(C═NR³³³¹)NR^(222a1)R^(333a1),    —NR²²²¹(C═NR³³³¹)OR^(222a1), —NR²²²¹(C═NR³³³¹)SR^(333a1),    —O(C═O)OR²²²¹, —O(C═O)NR²²²¹R³³³¹, —O(C═O)SR²²²¹, —S(C═O)OR²²²¹,    —P(O)OR²²²¹OR³³³¹, or —S(C═O)NR²²²¹R³³³¹ substituents; or    aryl-(C₀₋₁₀)alkyl, aryl-(C₂₋₁₀)alkenyl, or aryl-(C₂₋₁₀)alkynyl, any    of which is optionally substituted with one or more independent    halo, —CF₃, —OCF₃, —OR²²²¹, —N²²²¹R³³³¹(R^(333a1))_(j5a),    —C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j5a)R²²²¹,    —SO₂NR²²²¹R³³³¹, NR²²²¹(C═O)R³³³¹, NR²²²¹(C═O)OR³³³¹,    NR²²²¹(C═O)NR²²²¹R³³³¹, NR²²²¹S(O)_(j5a)R³³³¹, —(C═S)OR²²²¹,    —(C═O)SR²²²¹, —NR²²²¹(C═NR³³³¹)NR^(222a1)R^(333a1), —NR²²²¹    (C═NR³³³¹)OR^(222a1), —NR²²²¹(C═NR³³³¹)SR^(333a1), —O(C═O)OR²²²¹,    —O(C═O)NR²²²¹R³³³¹, —O(C═O)SR²²²¹, —S(C═O)OR²²²¹, —P(O)OR²²²¹R³³³¹,    or —S(C═O)NR²²²¹R³³³¹ substituents; or hetaryl-(C₀₋₁₀) alkyl,    hetaryl-(C₂₋₁₀)alkenyl, or hetaryl-(C₂₋₁₀)alkynyl, any of which is    optionally substituted with one or more independent halo, —CF₃,    —OCF₃, —OR²²²¹, NR²²²¹R³³³¹(R^(333a))_(j6a), —C(O)R²²²¹, —CO₂R²²²¹,    —CONR²²²¹R³³³¹, —NO₂, —CN, —S(O)_(j6a)R²²²¹, —SO₂NR²²²¹R³³³¹,    NR²²²¹(C═O)R³³³¹, NR²²²¹(C═O)OR³³³¹, NR²²²¹(C═O)NR²²²¹R³³³¹,    NR²²²¹S(O)_(j6a)R³³³¹, —(C═S)OR²²²¹, —(C═O)SR²²²¹, —NR²²²¹    (C═NR³³³¹)NR^(222a1)R^(333a1), —NR²²²¹(C═NR³³³¹)OR^(222a1),    —NR²²²¹(C═NR³³³¹)SR^(333a1), —O(C═O)OR²²²¹, —O(C═O)NR²²²¹R³³³¹,    —O(C═O)SR²²²¹, —S(C═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or    —S(C═O)NR²²²¹R³³³¹ substituents; or G¹¹ is taken together with the    carbon to which it is attached to form a double bond which is    substituted with R⁵ and G¹¹;-   R², R^(2a), R³, R^(3a), R²²², R²²²a, R³³³, R^(333a), R²¹, R^(2a1),    R³¹, R^(3a1), R²²²¹, R^(222a1), R³³³¹, and R^(333a1) are each    independently equal to (C₀₋₁₀)alkyl, (C₂₋₁₀)alkenyl, (C₂₋₁₀)alkynyl,    (C₁₋₁₀)alkoxy(C₁₋₁₀)alkyl, (C₁₋₁₀)alkoxy(C₂₋₁₀)alkenyl,    (C₁₋₁₀)alkoxy(C₂₋₁₀)alkynyl, (C₁₋₁₀)alkylthio(C₁₋₁₀)alkyl,    (C₁₋₁₀)alkylthio(C₂₋₁₀)alkenyl, (C₁₋₁₀)alkylthio(C₂₋₁₀)alkynyl,    cyclo(C₃₋₈)alkyl, cyclo(C₃₋₈)alkenyl, cyclo(C₃₋₈)alkyl(C₁₋₁₀)alkyl,    cyclo(C₃₋₈)alkenyl(C₁₋₁₀)alkyl, cyclo(C₃₋₈)alkyl(C₂₋₁₀)alkenyl,    cyclo(C₃₋₈)alkenyl(C₂₋₁₀)alkenyl, cyclo(C₃₋₈)alkyl(C₂₋₁₀)alkynyl,    cyclo(C₃₋₈)alkenyl(C₂₋₁₀)alkynyl, heterocyclyl-(C₀₋₁₀)alkyl,    heterocyclyl-(C₂₋₁₀)alkenyl, or heterocyclyl-(C₂₋₁₀)alkynyl, any of    which is optionally substituted by one or more G¹¹¹ substituents; or    aryl-(C₀₋₁₀)alkyl, aryl-(C₂₋₁₀)alkenyl, or aryl-(C₂₋₁₀)alkynyl,    hetaryl-(C₀₋₁₀)alkyl, hetaryl-(C₂₋₁₀)alkenyl, or    hetaryl-(C₂₋₁₀)alkynyl, any of which is optionally substituted by    one or more G¹¹¹ substituents; or in the case of —NR²R³(R^(3a))_(j1)    or —NR²²²R³³³(R³³³a)_(j1a) or —NR²²²R³³³(R³³³a)_(j2a) or    —NR²²²¹R³³³¹(R^(333a1))_(j3a) or —NR²²²¹R³³³¹(R^(333a1))_(j4a) or    —NR²²²¹R³³³¹(R^(333a1))_(j5a) or —NR²²²¹R³³³¹(R^(333a1))_(j6a), R²    and R³ or R²²² and R³³³, or R²²²¹ and R³³³¹ taken together with the    nitrogen atom to which they are attached form a 3-10 membered    saturated ring, unsaturated ring, heterocyclic saturated ring, or    heterocyclic unsaturated ring, wherein said ring is optionally    substituted by one or more G¹¹¹ substituents;-   X¹ and Y¹ are each independently —O—, —NR⁷—, —S(O)_(j7)—, —CR⁵R⁶—,    —N(C(O)OR⁷)—, —N(C(O)R⁷)—, —N(SO₂R⁷)—, —CH₂O—, —CH₂S—, —CH₂N(R⁷)—,    —CH(NR⁷)—, —CH₂N(C(O)R⁷)—, —CH₂N(C(O)OR⁷)—, —CH₂N(SO₂R⁷)—,    —CH(NHR⁷)—, —CH(NHC(O)R⁷)—, —CH(NHSO₂R⁷)—, —CH(NHC(O)OR⁷)—,    —CH(OC(O)R⁷)—, —CH(OC(O)NHR⁷)—, —CH═CH—, —C.ident.C—, —C(═NOR⁷)—,    —C(O)—, —CH(OR⁷)—, —C(O)N(R⁷)—, —N(R⁷)C(O)—, —N(R⁷)S(O)—,    —N(R⁷)S(O)₂—, —OC(O)N(R⁷)—, —N(R⁷)C(O)N(R⁷)—, —NR⁷C(O)O—,    —S(O)N(R⁷)—, —S(O)₂N(R⁷)—, —N(C(O)R⁷)S(O)—, —N(C(O)R⁷)S(O)₂—,    —N(R⁷)S(O)N(R⁷)—, —N(R⁷)S(O)₂N(R⁷)—, —C(O)N(R⁷)C(O)—,    —S(O)N(R⁷)C(O)—, —S(O)₂N(R⁷)C(O)—, —OS(O)N(R⁷)—, —OS(O)₂N(R⁷)—,    —N(R⁷)S(O)O—, —N(R⁷)S(O)₂O—, —N(R⁷)S(O)C(O)—, —N(R⁷)S(O)₂C(O)—,    —SON(C(O)R⁷)—, —SO₂N(C(O)R⁷)—, —N(R⁷)SON(R⁷)—, —N(R⁷)SO₂N(R⁷)—,    —C(O)O—, —N(R⁷)P(OR⁸)O—, —N(R⁷)P(OR⁸)—, —N(R⁷)P(O)(OR⁸)O—,    —N(R⁷)P(O)(OR⁸)—, —N(C(O)R⁷)P(OR⁸)O—, —N(C(O)R⁷)P(OR⁸)—,    —N(C(O)R⁷)P(O)(OR⁸)O—, —N(C(O)R⁷)P(OR⁸)—, —CH(R⁷)S(O)—,    —CH(R⁷)S(O)₂—, —CH(R⁷)N(C(O)OR⁷)—, —CH(R⁷)N(C(O)R⁷)—,    —CH(R⁷)N(SO₂R⁷)—, —CH(R⁷)O—, —CH(R⁷)S—, —CH(R⁷)N(R⁷)—,    —CH(R⁷)NC(O)R⁷)—, —CH(R⁷) NC(O)R⁷)—, —CH(R⁷)N(SO₂R⁷)—,    —CH(R⁷)C(═NOR⁷)—, —CH(R⁷)C(O)—, —CH(R⁷)CH(OR⁷)—, —CH(R⁷)C(O)N(R⁷)—,    —CH(R⁷)N(R⁷)C(O)—, —CH(R⁷)N(R⁷)S(O)—, —CH(R⁷)N(R⁷)S(O)₂—,    —CH(R⁷)OC(O)N(R⁷)—, —CH(R⁷)N(R⁷)C(O)N(R⁷)—, —CH(R⁷)NR⁷C(O)O—,    —CH(R⁷)S(O)N(R⁷)—, —CH(R⁷)S(O)₂N(R⁷)—, —CH(R⁷)N(C(O)R⁷)S(O)—,    —CH(R⁷)N(C(O)R⁷)S(O)—, —CH(R⁷)N(R⁷)S(O)N(R⁷)—,    —CH(R⁷)N(R⁷)S(O)₂N(R⁷)—, —CH(R⁷)C(O)N(R⁷)C(O)—,    —CH(R⁷)S(O)N(R⁷)C(O)—, —CH(R⁷)S(O)₂N(R⁷)C(O)—, —CH(R⁷)OS(O)N(R⁷)—,    —CH(R⁷)OS(O)₂N(R⁷)—, —CH(R⁷)N(R⁷)S(O)O—, —CH(R⁷)N(R⁷)S(O)₂O—,    —CH(R⁷)N(R⁷)S(O)C(O)—, —CH(R⁷)N(R⁷)S(O)₂C(O)—, —CH(R⁷)SON(C(O)R⁷)—,    —CH(R⁷)SO₂N(C(O)R⁷)—, —CH(R⁷)N(R⁷) SON(R⁷)—, —CH(R⁷)N(R⁷)SO₂N(R⁷)—,    —CH(R⁷)C(O)O—, —CH(R⁷)N(R⁷)P(OR⁸)O—, —CH(R⁷)N(R⁷)P(OR⁸)—,    —CH(R⁷)N(R⁷)P(O)(OR⁸)O—, —CH(R⁷)N(R⁷)P(O)(OR⁸)—,    —CH(R⁷)N(C(O)R⁷)P(OR⁸)O—, —CH(R⁷)N(C(O)R⁷)P(OR⁸)—,    —CH(R⁷)N(C(O)R⁷)P(O)(OR⁸)O—, or —CH(R⁷)N(C(O)R⁷)P(OR⁸)—;-   or X¹ and Y¹ are each independently represented by one of the    following structural formulas:

-   R¹⁰, taken together with the phosphinamide or phosphonamide, is a    5-, 6-, or 7-membered aryl, heteroaryl or heterocyclyl ring system;-   R⁵, R⁶, and G¹¹¹ are each independently a (C₀₋₁₀)alkyl,    (C₂₋₁₀)alkenyl, (C₂₋₁₀)alkynyl, (C₁₋₁₀)alkoxy(C₁₋₁₀)alkyl,    (C₁₋₁₀)alkoxy(C₂₋₁₀)alkenyl, (C₁₋₁₀)alkoxy(C₂₋₁₀)alkynyl,    (C₁₋₁₀)alkylthio(C₁₋₁₀)alkyl, (C₁₋₁₀)alkylthio(C₂₋₁₀)alkenyl,    (C₁₋₁₀)alkylthio(C₂₋₁₀)alkynyl, cyclo(C₃₋₈)alkyl,    cyclo(C₃₋₈)alkenyl, cyclo(C₃₋₈)alkyl(C₁₋₁₀)alkyl,    cyclo(C₃₋₈)alkenyl(C₁₋₁₀)alkyl, cyclo(C₃₋₈)alkyl(C₂₋₁₀)alkenyl,    cyclo(C₃₋₈)alkenyl(C₂₋₁₀)alkenyl, cyclo(C₃₋₈)alkyl(C₂₋₁₀)alkynyl,    cyclo(C₃₋₈)alkenyl(C₂₋₁₀)alkynyl, heterocyclyl-(C₀₋₁₀)alkyl,    heterocyclyl-(C₂₋₁₀)alkenyl, or heterocyclyl-(C₂₋₁₀)alkynyl, any of    which is optionally substituted with one or more independent halo,    —CF₃, —OCF₃, —OR⁷⁷, —NR⁷⁷R⁸⁷, —C(O)R⁷⁷, —CO₂R⁷⁷, —CONR⁷⁷R⁸⁷, —NO₂,    —CN, —S(O)_(j5a)R⁷⁷, —SO₂NR⁷⁷R⁸⁷, NR⁷⁷(C═O)R⁸⁷, NR⁷⁷(C═O)OR⁸⁷,    NR⁷⁷(C═O)NR⁷⁸R⁸⁷, NR⁷⁷S(O)_(j5a)R⁸⁷, —(C═S)OR⁷⁷, —(C═O)SR⁷⁷,    —NR⁷⁷(C═NR⁸⁷)NR⁷⁸R⁸⁸, —NR⁷⁷(C═NR⁸⁷)OR⁷⁸, —NR⁷⁷(C═NR⁸⁷)SR⁷⁸,    —O(C═O)OR⁷⁷, —O(C═O)NR⁷⁷R⁸⁷, —O(C═O)SR⁷⁷, —S(C═O)OR⁷⁷,    —P(O)OR⁷⁷OR⁸⁷, or —S(C═O)NR⁷⁷R⁸⁷ substituents; or aryl-(C₀₋₁₀)alkyl,    aryl-(C₂₋₁₀)alkenyl, or aryl-(C₂₋₁₀)alkynyl, any of which is    optionally substituted with one or more independent halo, —CF₃,    —OCF₃, —OR⁷⁷, —NR⁷⁷R⁸⁷, —C(O)R⁷⁷, —CO₂R⁷⁷, —CONR⁷⁷R⁸⁷, —NO₂, —CN,    —S(O)_(j5a)R⁷⁷, —SO₂NR⁷⁷R⁸⁷, NR⁷⁷(C═O)R⁸⁷, NR⁷⁷(C═O)OR⁸⁷,    NR⁷⁷(C═O)NR⁷⁸R⁸⁷, NR⁷⁷S(O)_(j5a)R⁸⁷, —(C═S)OR⁷⁷, —(C═O)SR⁷⁷,    —NR⁷⁷(C═NR⁸⁷)NR⁷⁸R⁸⁸, —NR⁷⁷(C═NR⁸⁷)OR⁷⁸, —NR⁷⁷(C═NR⁸⁷)SR⁷⁸,    —O(C═O)OR⁷⁷, —O(C═O)NR⁷⁷R⁸⁷, —O(C═O)SR⁷⁷, —S(C═O)OR⁷⁷, —P(O)OR⁷⁷R⁸⁷,    or —S(C═O)NR⁷⁷R⁸⁷ substituents; or hetaryl-(C₀₋₁₀)alkyl,    hetaryl-(C₂₋₁₀)alkenyl, or hetaryl-(C₂₋₁₀)alkynyl, any of which is    optionally substituted with one or more independent halo, —CF₃,    —OCF₃, —OR⁷⁷, —NR⁷⁷R⁸⁷, —C(O)R⁷⁷, —CO₂R⁷⁷, —CONR⁷⁷R⁸⁷, —NO₂, —CN,    —S(O)_(j5a)R⁷⁷, —SO₂NR⁷⁷R⁸⁷, NR⁷⁷(C═O)R⁸⁷, NR⁷⁷(C═O)OR⁸⁷,    NR⁷⁷(C═O)NR⁷⁸R⁸⁷, NR⁷⁷S(O)_(j5a)R⁸⁷, —(C═S)OR⁷⁷, —(C═O)SR⁷⁷,    —NR⁷⁷(C═NR⁸⁷)NR⁷⁸R⁸⁸, —NR⁷⁷(C═NR⁸⁷)OR⁷⁸, —NR⁷⁷(C═NR⁸⁷)SR⁷⁸,    —O(C═O)OR⁷⁷, —O(C═O)NR⁷⁷R⁸⁷, —O(C═O)SR⁷⁷, —S(C═O)OR⁷⁷,    —P(O)OR⁷⁷OR⁸⁷, or —S(C═O)NR⁷⁷R⁸⁷ substituents; or R⁵ with R⁶ taken    together with the respective carbon atom to which they are attached,    form a 3-10 membered saturated or unsaturated ring, wherein said    ring is optionally substituted with R⁶⁹; or R⁵ with R⁶ taken    together with the respective carbon atom to which they are attached,    form a 3-10 membered saturated or unsaturated heterocyclic ring,    wherein said ring is optionally substituted with R⁶⁹;-   R⁷ and R⁸ are each independently H, acyl, alkyl, alkenyl, aryl,    heteroaryl, heterocyclyl or cycloalkyl, any of which is optionally    substituted by one or more G¹¹¹ substituents;-   R⁴ is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl,    heterocyclyl, cycloalkenyl, or heterocycloalkenyl, any of which is    optionally substituted by one or more G⁴¹ substituents;-   R⁶⁹ is equal to halo, —OR⁷⁸, —SH, —NR⁷⁸R⁸⁸, —CO₂R⁷⁸, —CONR⁷⁸R⁸⁸,    —NO₂, —CN, —S(O)_(j8)R⁷⁸, —SO₂NR⁷⁸R⁸⁸, (C₀₋₁₀)alkyl, (C₂₋₁₀)alkenyl,    (C₂₋₁₀)alkynyl, (C₁₋₁₀)alkoxy(C₁₋₁₀)alkyl,    (C₁₋₁₀)alkoxy(C₂₋₁₀)alkenyl, (C₁₋₁₀)alkoxy(C₂₋₁₀)alkynyl,    (C₁₋₁₀)alkylthio(C₁₋₁₀)alkyl, (C₁₋₁₀)alkylthio(C₂₋₁₀)alkenyl,    (C₁₋₁₀)alkylthio(C₂₋₁₀)alkynyl, cyclo(C₃₋₈)alkyl,    cyclo(C₃₋₈)alkenyl, cyclo(C₃₋₈)alkyl(C₁₋₁₀)alkyl,    cyclo(C₃₋₈)alkenyl(C₁₋₁₀)alkyl, cyclo(C₃₋₈)alkyl(C₂₋₁₀)alkenyl,    cyclo(C₃₋₈)alkenyl(C₂₋₁₀)alkenyl, cyclo(C₃₋₈)alkyl(C₂₋₁₀)alkynyl,    cyclo(C₃₋₈)alkenyl(C₂₋₁₀)alkynyl, heterocyclyl-(C₀₋₁₀)alkyl,    heterocyclyl-(C₂₋₁₀)alkenyl, or heterocyclyl-(C₂₋₁₀)alkynyl, any of    which is optionally substituted with one or more independent halo,    cyano, nitro, —OR⁷⁷⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸, or —NR⁷⁷⁸R⁸⁸⁸ substituents; or    aryl-(C₀₋₁₀)alkyl, aryl-(C₂₋₁₀)alkenyl, or aryl-(C₂₋₁₀)alkynyl, any    of which is optionally substituted with one or more independent    halo, cyano, nitro, —OR⁷⁷⁸, (C₁₋₁₀)alkyl, (C₂₋₁₀)alkenyl,    (C₂₋₁₀)alkynyl, halo(C₁₋₁₀)alkyl, halo(C₂₋₁₀)alkenyl,    halo(C₂₋₁₀)alkynyl, —COOH, (C₁₋₄)alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸,    —SO₂NR⁷⁷⁸R⁸⁸⁸, or —NR⁷⁷⁸R⁸⁸⁸ substituents; or hetaryl-(C₀₋₁₀)alkyl,    hetaryl-(C₂₋₁₀)alkenyl, or hetaryl-(C₂₋₁₀)alkynyl, any of which is    optionally substituted with one or more independent halo, cyano,    nitro, —OR⁷⁷⁸, (C₁₋₁₀)alkyl, (C₂₋₁₀)alkenyl, (C₂₋₁₀)alkynyl,    halo(C₁₋₁₀)alkyl, halo(C₂₋₁₀)alkenyl, halo(C₂₋₁₀)alkynyl, —COOH,    (C₁₋₄)alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸, or —NR⁷⁷⁸R⁸⁸⁸    substituents; or mono(C₁₋₆alkyl)amino(C₁₋₆)alkyl,    di((C₁₋₆)alkyl)amino(C₁₋₆)alkyl, mono(aryl)amino(C₁₋₆)alkyl,    di(aryl)amino(C₁₋₆)alkyl, or —N((C₁₋₆)alkyl)-(C₁₋₆)alkyl-aryl, any    of which is optionally substituted with one or more independent    halo, cyano, nitro, —OR⁷⁷⁸, (C₁₋₁₀)alkyl, (C₂₋₁₀)alkenyl,    (C₂₋₁₀)alkynyl, halo(C₁₋₁₀)alkyl, halo(C₂₋₁₀)alkenyl,    halo(C₂₋₁₀)alkynyl, —COOH, (C₁₋₄)alkoxycarbonyl,    —CONR⁷⁷⁸R⁸⁸⁸SO₂NR⁷⁷⁸R⁸⁸⁸, or —NR⁷⁷⁸R⁸⁸⁸ substituents; or in the case    of —NR⁷⁸R⁸⁸, R⁷⁸ and R⁸⁸ taken together with the nitrogen atom to    which they are attached form a 3-10 membered saturated ring,    unsaturated ring, heterocyclic saturated ring, or heterocyclic    unsaturated ring, wherein said ring is optionally substituted with    one or more independent halo, cyano, hydroxy, nitro, (C₁₋₁₀)alkoxy,    —SO₂NR⁷⁷⁸R⁸⁸⁸, or —NR⁷⁷⁸R⁸⁸⁸ substituents;-   R⁷⁷, R⁷⁸, R⁸⁷, R⁸⁸, R⁷⁷⁸, and R⁸⁸⁸ are each independently    (C₀₋₁₀)alkyl, (C₂₋₁₀)alkenyl, (C₂₋₁₀)alkynyl,    (C₁₋₁₀)alkoxy(C₁₋₁₀)alkyl, (C₁₋₁₀)alkoxyC₂₋₁₀)alkenyl,    (C₁₋₁₀)alkoxy(C₂₋₁₀)alkynyl, (C₁₋₁₀)alkylthio(C₁₋₁₀)alkyl,    (C₁₋₁₀)alkylthio(C₂₋₁₀)alkenyl, (C₁₋₁₀)alkylthio(C₂₋₁₀)alkynyl,    cyclo(C₃₋₈)alkyl, cyclo(C₃₋₈)alkenyl, cyclo(C₃₋₈)alkyl(C₁₋₁₀)alkyl,    cyclo(C₃₋₈)alkenyl(C₁₋₁₀)alkyl, cyclo(C₃₋₈)alkyl(C₂₋₁₀)alkenyl,    cyclo(C₃₋₈)alkenyl(C₂₋₁₀)alkenyl, cyclo(C₃₋₈)alkyl(C₂₋₁₀)alkynyl,    cyclo(C₃₋₈)alkenyl(C₂₋₁₀)alkynyl, heterocyclyl-(C₀₋₁₀)alkyl,    heterocyclyl-(C₂₋₁₀)alkenyl, heterocyclyl-(C₂₋₁₀)alkynyl,    (C₁₋₁₀)alkylcarbonyl, (C₂₋₁₀)alkenylcarbonyl,    (C₂₋₁₀)alkynylcarbonyl, (C₁₋₁₀)alkoxycarbonyl,    (C₁₋₁₀)alkoxycarbonyl(C₁₋₁₀)alkyl, mono(C₁₋₆)alkylaminocarbonyl,    di(C₁₋₆)alkylaminocarbonyl, mono(aryl)aminocarbonyl,    di(aryl)aminocarbonyl, or (C₁₋₁₀)alkyl(aryl)aminocarbonyl, any of    which is optionally substituted with one or more independent halo,    cyano, hydroxy, nitro, (C₁₋₁₀)alkoxy,    —SO₂N((C₀₋₄)alkyl)((C₀₋₄)alkyl), or —N((C₀₋₄)alkyl)((C₀₋₄)alkyl)    substituents; or aryl-(C₀₋₁₀)alkyl, aryl-(C₂₋₁₀)alkenyl, or    aryl-(C₂₋₁₀)alkynyl, any of which is optionally substituted with one    or more independent halo, cyano, nitro, —O((C₀₋₄)alkyl),    (C₁₋₁₀)alkyl, (C₂₋₁₀)alkenyl, (C₂₋₁₀)alkynyl, halo(C₁₋₁₀)alkyl,    halo(C₂₋₁₀)alkenyl, halo(C₂₋₁₀)alkynyl, —COOH, (C₁₋₄)alkoxycarbonyl,    —CON((C₀₋₄)alkyl)((C₀₋₁₀)alkyl), —SO₂N((C₀₋₄)alkyl)((C₀₋₄)alkyl), or    —N((C₀₋₄)alkyl)((C₀₋₄)alkyl) substituents; or hetaryl-(C₀₋₁₀)alkyl,    hetaryl-(C₂₋₁₀)alkenyl, or hetaryl-(C₂₋₁₀)alkynyl, any of which is    optionally substituted with one or more independent halo, cyano,    nitro, —O((C₀₋₄)alkyl), (C₁₋₁₀)alkyl, (C₂₋₁₀)alkenyl,    (C₂₋₁₀)alkynyl, halo(C₁₋₁₀)alkyl, halo(C₂₋₁₀)alkenyl,    halo(C₂₋₁₀)alkynyl, —COOH, (C₁₋₄)alkoxycarbonyl,    —CON((C₀₋₄)alkyl)((C₀₋₄)alkyl), —SO₂N((C₀₋₄)alkyl)((C₀₋₄)alkyl), or    —N((C₀₋₄)alkyl)((C₀₋₄)alkyl) substituents; or    mono((C₁₋₆)alkyl)amino(C₁₋₆)alkyl, di((C₁₋₆)alkyl)amino(C₁₋₆)alkyl,    mono(aryl)amino(C₁₋₆)alkyl, di(aryl)amino(C₁₋₆)alkyl, or    —N((C₁₋₆)alkyl)-(C₁₋₆)alkyl-aryl, any of which is optionally    substituted with one or more independent halo, cyano, nitro,    —O((C₀₋₄)alkyl), (C₁₋₁₀)alkyl, (C₂₋₁₀)alkenyl, (C₂₋₁₀)alkynyl,    halo(C₁₋₁₀)alkyl, halo(C₂₋₁₀)alkenyl, halo(C₂₋₁₀)alkynyl, —COOH,    (C₁₋₄)alkoxycarbonyl, —CON((C₀₋₄)alkyl)((C₀₋₄)alkyl),    —SO₂N((C₀₋₄)alkyl)((C₀₋₄)alkyl), or —N((C₀₋₄)alkyl)((C₀₋₄)alkyl)    substituents; and-   n, m, j1, j1a, j2a, j3a, j4, j4a, j5a, j6a, j7, and j8 are each    independently equal to 0, 1, or 2.

In an embodiment, the BTK inhibitor is a compound selected from thestructures disclosed in U.S. Pat. Nos. 8,450,335 and 8,609,679, and U.S.Patent Application Publication Nos. 2010/0029610 A1, 2012/0077832 A1,2013/0065879 A1, 2013/0072469 A1, and 2013/0165462 A1, the disclosuresof which are incorporated by reference herein. In an embodiment, the BTKinhibitor is a compound of Formula (XXV) or Formula (XXVI):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, wherein:

-   Ring A is an optionally substituted group selected from phenyl, a    3-7 membered saturated or partially unsaturated carbocyclic ring, an    8-10 membered bicyclic saturated, partially unsaturated or aryl    ring, a 5-6 membered monocyclic heteroaryl ring having 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    a 4-7 membered saturated or partially unsaturated heterocyclic ring    having 1-3 heteroatoms independently selected from nitrogen, oxygen,    or sulfur, an optionally substituted 7-10 membered bicyclic    saturated or partially unsaturated heterocyclic ring having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms    independently selected from nitrogen, oxygen, or sulfur;-   Ring B is an optionally substituted group selected from phenyl, a    3-7 membered saturated or partially unsaturated carbocyclic ring, an    8-10 membered bicyclic saturated, partially unsaturated or aryl    ring, a 5-6 membered monocyclic heteroaryl ring having 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    a 4-7 membered saturated or partially unsaturated heterocyclic ring    having 1-3 heteroatoms independently selected from nitrogen, oxygen,    or sulfur, an optionally substituted 7-10 membered bicyclic    saturated or partially unsaturated heterocyclic ring having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms    independently selected from nitrogen, oxygen, or sulfur;-   R¹ is a warhead group;-   R^(y) is hydrogen, halogen, —CN, —CF₃, C₁₋₄ aliphatic, C₁₋₄    haloaliphatic, —OR, —C(O)R, or —C(O)N(R)₂;-   each R group is independently hydrogen or an optionally substituted    group selected from C₁₋₆ aliphatic, phenyl, an optionally    substituted 4-7 membered heterocyclic ring having 1-2 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, or a 5-6    membered monocyclic heteroaryl ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur;-   W¹ and W² are each independently a covalent bond or a bivalent C₁₋₃    alkylene chain wherein one methylene unit of W¹ or W² is optionally    replaced by —NR²—, —N(R²)C(O)—, —C(O)N(R²)—, —N(R²)SO₂—, —SO₂N(R²),    —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO— or —SO₂—;-   R² is hydrogen, optionally substituted C₁₋₆ aliphatic, or —C(O)R,    or:-   R² and a substituent on Ring A are taken together with their    intervening atoms to form a 4-6 membered saturated, partially    unsaturated, or aromatic fused ring, or:-   R² and R^(y) are taken together with their intervening atoms to form    an optionally substituted 4-7 membered partially unsaturated or    aromatic fused ring;-   m and p are independently 0-4; and-   R^(x) and R^(v) are independently selected from —R, halogen, —OR,    —O(CH₂)_(q)OR, —CN, —NO₂, —SO₂R, —SO₂N(R)₂, —SOR, —C(O)R, —CO₂R,    —C(O)N(R)₂, —NRC(O)R, —NRC(O)NR₂, —NRSO₂R, or —N(R)₂, wherein q is    1-4; or:-   R^(x) and R¹ when concurrently present on Ring B are taken together    with their intervening atoms to form an optionally substituted 5-7    membered saturated, partially unsaturated, or aryl ring having 0-3    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    wherein said ring is substituted with a warhead group and 0-3 groups    independently selected from oxo, halogen, —CN, or C₁₋₆ aliphatic; or-   R^(v) and R¹ when concurrently present on Ring A are taken together    with their intervening atoms to form an optionally substituted 5-7    membered saturated, partially unsaturated, or aryl ring having 0-3    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    wherein said ring is substituted with a warhead group and 0-3 groups    independently selected from oxo, halogen, —CN, or C₁₋₆ aliphatic.

In an embodiment, the BTK inhibitor is a compound of Formula (XXV) orFormula (XXVI), wherein:

-   Ring A is selected from phenyl, a 3-7 membered saturated or    partially unsaturated carbocyclic ring, an 8-10 membered bicyclic    saturated, partially unsaturated or aryl ring, a 5-6 membered    monocyclic heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, or sulfur, an optionally substituted    4-7 membered saturated or partially unsaturated heterocyclic ring    having 1-3 heteroatoms independently selected from nitrogen, oxygen,    or sulfur, an optionally substituted 7-10 membered bicyclic    saturated or partially unsaturated heterocyclic ring having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms    independently selected from nitrogen, oxygen, or sulfur;-   Ring B is selected from phenyl, a 3-7 membered saturated or    partially unsaturated carbocyclic ring, an 8-10 membered bicyclic    saturated, partially unsaturated or aryl ring, a 5-6 membered    monocyclic heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, or sulfur, an optionally substituted    4-7 membered saturated or partially unsaturated heterocyclic ring    having 1-3 heteroatoms independently selected from nitrogen, oxygen,    or sulfur, an optionally substituted 7-10 membered bicyclic    saturated or partially unsaturated heterocyclic ring having 1-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms    independently selected from nitrogen, oxygen, or sulfur;-   R¹ is -L-Y, wherein:-   L is a covalent bond or a bivalent C₁₋₈ saturated or unsaturated,    straight or branched, hydrocarbon chain, wherein one, two, or three    methylene units of L are optionally and independently replaced by    cyclopropylene, —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO₂—, —SO₂N(R)—,    —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO₂—, —C(═S)—, —C(═NR)—,    —N═N—, or —C(═N₂)—;-   Y is hydrogen, C₁₋₆ aliphatic optionally substituted with oxo,    halogen, or CN, or a 3-10 membered monocyclic or bicyclic,    saturated, partially unsaturated, or aryl ring having 0-3    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    and wherein said ring is substituted with at 1-4 groups    independently selected from -Q-Z, oxo, NO₂, halogen, CN, or C₁₋₆    aliphatic, wherein:-   Q is a covalent bond or a bivalent C₁₋₆ saturated or unsaturated,    straight or branched, hydrocarbon chain, wherein one or two    methylene units of Q are optionally and independently replaced by    —NR—, —S—, —O—, —C(O)—, —SO—, or —SO₂—; and-   Z is hydrogen or C₁₋₆ aliphatic optionally substituted with oxo,    halogen, or CN;-   R^(y) is hydrogen, halogen, —CN, —CF₃, C₁₋₄ aliphatic, C₁₋₄    haloaliphatic, —OR, —C(O)R, or —C(O)N(R)₂;-   each R group is independently hydrogen or an optionally substituted    group selected from C₁₋₆ aliphatic, phenyl, an optionally    substituted 4-7 membered heterocylic ring having 1-2 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, or a 5-6    membered monocyclic heteroaryl ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur;-   W¹ and W² are each independently a covalent bond or a bivalent C₁₋₃    alkylene chain wherein one methylene unit of W¹ or W² is optionally    replaced by —NR²—, —N(R²)C(O)—, —C(O)N(R²)—, —N(R²)SO₂—, —SO₂N(R²)—,    —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO— or —SO₂—;-   R² is hydrogen, optionally substituted C₁₋₆ aliphatic, or —C(O)R,    or:-   R² and a substituent on Ring A are taken together with their    intervening atoms to form a 4-6 membered partially unsaturated or    aromatic fused ring; or-   R² and R^(y) are taken together with their intervening atoms to form    a 4-6 membered saturated, partially unsaturated, or aromatic fused    ring;-   m and p are independently 0-4; and-   R^(x) and R^(v) are independently selected from —R, halogen, —OR,    —O(CH₂)_(q)OR, —CN, —NO₂, —SO₂R, —SO₂N(R)₂, —SOR, —C(O)R, —CO₂R,    —C(O)N(R)₂, —NRC(O)R, —NRC(O)NR₂, —NRSO₂R, or —N(R)₂, wherein R is    independently selected from the group consisting of hydrogen,    cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, and    heterocycly; or:-   R^(x) and R¹ when concurrently present on Ring B are taken together    with their intervening atoms to form a 5-7 membered saturated,    partially unsaturated, or aryl ring having 0-3 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, wherein    said ring is substituted with a warhead group and 0-3 groups    independently selected from oxo, halogen, —CN, or C₁₋₆ aliphatic; or-   R^(v) and R¹ when concurrently present on Ring A are taken together    with their intervening atoms to form a 5-7 membered saturated,    partially unsaturated, or aryl ring having 0-3 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, wherein    said ring is substituted with a warhead group and 0-3 groups    independently selected from oxo, halogen, —CN, or C₁₋₆ aliphatic.

As defined generally above, Ring A is selected from phenyl, a 3-7membered saturated or partially unsaturated carbocyclic ring, an 8-10membered bicyclic saturated, partially unsaturated or aryl ring, a 5-6membered monocyclic heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, an optionally substituted 4-7membered saturated or partially unsaturated heterocyclic ring having 1-3heteroatoms independently selected from nitrogen, oxygen, or sulfur, anoptionally substituted 7-10 membered bicyclic saturated or partiallyunsaturated heterocyclic ring having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclicheteroaryl ring having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

In preferred embodiments, Ring A is an optionally substituted phenylgroup. In some embodiments, Ring A is an optionally substituted naphthylring or an optionally substituted bicyclic 8-10 membered heteroaryl ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur. In certain other embodiments, Ring A is an optionallysubstituted 3-7 membered carbocyclic ring. In yet other embodiments,Ring A is an optionally substituted 4-7 membered heterocyclic ringhaving 1-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur. In preferred embodiments, Ring B is an optionally substitutedphenyl group.

In certain embodiments, Ring A in Formula (XXV) or Formula (XXVI) issubstituted as defined herein. In some embodiments, Ring A issubstituted with one, two, or three groups independently selected fromhalogen, R^(o), or —(CH₂)₀₋₄OR^(o), or —O(CH₂)₀₋₄R^(o), wherein eachR^(o) is independently selected from the group consisting of cycloalkyl,alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl.Exemplary substituents on Ring A include Br, I, Cl, methyl, —CF₃, —C≡CH,—OCH₂phenyl, —OCH₂(fluorophenyl), or —OCH₂pyridyl.

In a preferred embodiment, the BTK inhibitor is CC-292, or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, preferably a hydrochloride salt or a besylate saltthereof. In a preferred embodiment, the BTK inhibitor is a compound ofFormula (XXVII):

which isN-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide,or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, or in an exemplary embodiment is a hydrochloride saltor a besylate salt thereof. The preparation of this compound isdescribed in U.S. Patent Application Publication No. 2010/0029610 A1 atExample 20, the disclosure of which is incorporated by reference herein.The preparation of the besylate salt of this compound is described inU.S. Patent Application Publication No. 2012/0077832 A1, the disclosureof which is incorporated by reference herein. In an embodiment, the BTKinhibitor is a compound selected from the structures disclosed in U.S.Patent Application Publication No. 2010/0029610 A1 or No. 2012/0077832A1, the disclosures of which are incorporated by reference herein.

In a preferred embodiment, the BTK inhibitor isN-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamideor a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, or a hydrochloride salt thereof. The preparation ofthis compound is described in U.S. Patent Application Publication Nos.2010/0029610 A1 and 2012/0077832 A1, the disclosure of which isincorporated by reference herein.

In a preferred embodiment, the BTK inhibitor is(N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide),or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, or preferably a besylate salt thereof. The preparationof this compound is described in U.S. Patent Application Publication No.2010/0029610 A1 at Example 20, the disclosure of which is incorporatedby reference herein. The preparation of its besylate salt is describedin U.S. Patent Application Publication No. 2012/0077832 A1, thedisclosure of which is incorporated by reference herein.

In an embodiment, the BTK inhibitor is a compound of Formula (XXVIII):

or a pharmaceutically acceptable salt, hydrate, solvate, cocrystal, orprodrug thereof, wherein

-   L represents (1) —O—, (2) —S—, (3) —SO—, (4) —SO₂— (5) —NH—, (6)    —C(O)—, (7) —CH₂O—, (8) —O—CH₂—, (9) —CH₂—, or (10) —CH(OH)—;-   R¹ represents (1) a halogen atom, (2) a C₁₋₄ alkyl group, (3) a C₁₋₄    alkoxy group, (4) a C₁₋₄ haloalkyl group, or (5) a C₁₋₄ haloalkoxy    group;-   ring1 represents a 4- to 7-membered cyclic group, which may be    substituted by from one to five substituents each independently    selected from the group consisting of (1) halogen atoms, (2) C₁₋₄    alkyl groups, (3) C₁₋₄ alkoxy groups, (4) nitrile, (5) C₁₋₄    haloalkyl groups, and (6) C₁₋₄ haloalkoxy groups, wherein when two    or more substituents are present on ring1, these substituents may    form a 4- to 7-membered cyclic group together with the atoms in    ring1 to which these substituents are bound;-   ring2 represents a 4- to 7-membered saturated heterocycle, which may    be substituted by from one to three -K-R²; K represents (1) a    bond, (2) a C₁₋₄ alkylene, (3) —C(O)—, (4) —C(O)—CH₂—, (5)    —CH₂—C(O)—, (6) —C(O)O—, or (7) —SO₂— (wherein the bond on the left    is bound to the ring2);-   R² represents (1) a C₁₋₄ alkyl, (2) a C₂₋₄ alkenyl, or (3) a C₂₋₄    alkynyl group, each of which may be substituted by from one to five    substituents each independently selected from the group consisting    of (1) NR³R⁴, (2) halogen atoms, (3) CONR⁵R⁶, (4) CO₂R⁷, and (5)    OR⁸;-   R³ and R⁴ each independently represent (1) a hydrogen atom, or (2) a    C₁₋₄ alkyl group which may be substituted by OR⁹ or CONR¹⁰R¹¹; R³    and R⁴ may, together with the nitrogen atom to which they are bound,    form a 4- to 7-membered nitrogenous saturated heterocycle, which may    be substituted by an oxo group or a hydroxyl group;-   R⁵ and R⁶ each independently represent (1) a hydrogen atom, (2) a    C₁₋₄ alkyl group, or (3) a phenyl group;-   R⁷ represents (1) a hydrogen atom or (2) a C₁₋₄ alkyl group;-   R⁸ represents (1) a hydrogen atom, (2) a C₁₋₄ alkyl group, (3) a    phenyl group, or (4) a benzotriazolyl group; R⁹ represents (1) a    hydrogen atom or (2) a C₁₋₄ alkyl group;-   R¹⁰ and R¹¹ each independently represent (1) a hydrogen atom or (2)    a C₁₋₄ alkyl group;-   n represents an integer from 0 to 4;-   m represents an integer from 0 to 2; and-   when n is two or more, the R¹'s may be the same as each other or may    differ from one another).

In an exemplary embodiment, the BTK inhibitor is a compound of Formula(XXVIII-A):

or a pharmaceutically acceptable salt, hydrate, solvate, cocrystal, orprodrug thereof, wherein

-   R¹ represents (1) a halogen atom, (2) a C₁₋₄ alkyl group, (3) a C₁₋₄    alkoxy group, (4) a C₁₋₄ haloalkyl group, or (5) a C₁₋₄ haloalkoxy    group;-   ring1 represents a benzene, cyclohexane, or pyridine ring, each of    which may be substituted by from one to five substituents each    independently selected from the group consisting of (1) halogen    atoms, (2) C₁₋₄ alkyl groups, (3) C₁₋₄ alkoxy groups, (4)    nitrile, (5) CF₃;-   ring2 represents a 4- to 7-membered nitrogenous saturated    heterocycle, which may be substituted by from one to three -K-R²;    wherein K represents (1) a bond, (2) a C₁₋₄ alkylene, (3)    —C(O)—, (4) —C(O)—CH₂—, (5) —CH₂—C(O)—, (6) —C(O)O—, or (7) —SO₂—    (wherein the bond on the left is bound to the ring2);-   R² represents (1) a C₁₋₄ alkyl, (2) a C₂₋₄ alkenyl, or (3) a C₂₋₄    alkynyl group, each of which may be substituted by from one to five    substituents each independently selected from the group consisting    of (1) NR³R⁴, (2) halogen atoms, (3) CONR⁵R⁶, (4) CO₂R⁷, and (5)    OR⁸;-   R³ and R⁴ each independently represent (1) a hydrogen atom, or (2) a    C₁₋₄ alkyl group which may be substituted by OR⁹ or CONR¹⁰R¹¹; R³    and R⁴ may, together with the nitrogen atom to which they are bound,    form a 4- to 7-membered nitrogenous saturated heterocycle, which may    be substituted by an oxo group or a hydroxyl group;-   R⁵ and R⁶ each independently represent (1) a hydrogen atom, (2) a    C₁₋₄ alkyl group, or (3) a phenyl group;-   R⁷ represents (1) a hydrogen atom or (2) a C₁₋₄ alkyl group;-   R⁸ represents (1) a hydrogen atom, (2) a C₁₋₄ alkyl group, (3) a    phenyl group, or (4) a benzotriazolyl group; R⁹ represents (1) a    hydrogen atom or (2) a C₁₋₄ alkyl group;-   R¹⁰ and R¹¹ each independently represent (1) a hydrogen atom or (2)    a C₁₋₄ alkyl group;-   n represents an integer from 0 to 4;-   m represents an integer from 0 to 2; and-   when n is two or more, the R¹'s may be the same as each other or may    differ from one another).

In a preferred embodiment, the BTK inhibitor is a compound of Formula(XXVIII-B):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, preferably a hydrochloride salt thereof. Thepreparation of this compound is described in International PatentApplication Publication No. WO 2013/081016 A1, the disclosure of whichis incorporated by reference herein. In an embodiment, the BTK inhibitoris6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7,9-dihydro-8H-purin-8-oneor a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, or preferably a hydrochloride salt thereof. In anembodiment, the BTK inhibitor is6-amino-9-[(3S)-1-(2-butynoyl)-3-pyrrolidinyl]-7-(4-phenoxyphenyl)-7,9-dihydro-8H-purin-8-oneor a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, or a hydrochloride salt thereof.

The R-enantiomer of Formula (XXVIII-B) is also known as ONO-4059, and isgiven by Formula (XXVIII-R). In a preferred embodiment, the BTKinhibitor is a compound of Formula (XXVIII-R):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, preferably a hydrochloride salt thereof.

In an embodiment, the BTK inhibitor is6-amino-9-[(3R)-1-(2-butynoyl)-3-pyrrolidinyl]-7-(4-phenoxyphenyl)-7,9-dihydro-8H-purin-8-oneor a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, preferably a hydrochloride salt thereof.

The preparation of Formula (XXVII-R) is described in InternationalPatent Application Publication No. WO 2013/081016 A1, the disclosure ofwhich is incorporated by reference herein. In brief, the BTK inhibitorof Formula (XXVIII-R) can be prepared by the following procedure.

Step 1: A solution of dibenzylamine (10.2 g) in dichloromethane (30 mL)is dripped into a solution of 4,6-dichloro-5-nitropyrimidine (10 g) indichloromethane (70 mL) on an ice bath. Then triethylamine (14.4 mL) isadded, and the mixture is stirred for 1 hour. Water is added to thereaction mixture, the organic layer is washed with a saturated aqueoussodium chloride solution and dried over anhydrous sodium sulfate, andthe solvent is concentrated under reduced pressure to obtainN,N-dibenzyl-6-chloro-5-nitropyrimidine-4-amine (19.2 g).

Step 2: The compound prepared in Step 1 (19 g) and tert-butyl(3R)-3-aminopyrrolidine-1-carboxylate (10.5 g) are dissolved in dioxane(58 mL). Triethylamine (8.1 mL) is added, and the mixture is stirred for5 hours at 50° C. The reaction mixture is returned to room temperature,the solvent is distilled off, water is added, and extraction isperformed with ethyl acetate. The organic layer is washed with saturatedaqueous sodium chloride solution, then dried over anhydrous sodiumsulfate, and the solvent is distilled off. The residue is purified bysilica gel column chromatography to obtain tert-butyl(3R)-3-{[6-(dibenzylamino)-5-nitropyrimidin-4-yl]amino}pyrrolid-ine-1-carboxylate(27.0 g).

Step 3: An ethyl acetate (360 mL) solution of the compound prepared inStep 2 (17.5 g) is dripped into a mixture of zinc (23.3 g) and a 3.0 Maqueous ammonium chloride solution (11.4 g) on an ice bath, and thetemperature is immediately raised to room temperature. After stirringfor 2 hours, the reaction mixture is filtered through CELITE and thesolvent is distilled off. The residue is purified by silica gel columnchromatography to obtain tert-butyl(3R)-3-{[5-amino-6-(dibenzylamino)pyrimidin-4-yl]amino}pyrrolidine-1-carboxylate(12.4 g).

Step 4: The compound prepared in Step 3 (8.4 g) and 1,1′-carbonyldiimidazole (5.9 g) are dissolved in tetrahydrofuran (120 mL) and thesolution is stirred for 15 hours at 60° C. The solvent is distilled offfrom the reaction mixture, water is added, and extraction with ethylacetate is performed. The organic layer is washed with saturated aqueoussodium chloride solution, dried over anhydrous sodium sulfate, and thesolvent is distilled off. The residue is purified by silica gel columnchromatography to obtain tert-butyl(3R)-3-[6-(dibenzylamino)-8-oxo-7,8-dihydro-9H-purin-9-yl]pyrrolidin-1-carboxylate(7.8 g).

Step 5: The compound prepared in Step 4 (7.8 g) is dissolved in methanol(240 mL) and ethyl acetate (50 mL), 20% Pearlman's catalyst (Pd(OH)₂/C)(8.0 g, 100 wt %) is added, hydrogen gas replacement is carried out, andstirring is performed for 7.5 hours at 60° C. The reaction mixture isfiltered through CELITE and the solvent is distilled off to obtaintert-butyl(3R)-3-(6-amino-8-oxo-7,8-dihydro-9H-purin-9-yl)pyrrolidine-1-carboxylate(5.0 g).

Step 6: At room temperature p-phenoxy phenyl boronic acid (2.1 g),copper(II) acetate (1.48 g), molecular sieve 4A (2.5 g), and pyridine(0.82 mL) are added to a dichloromethane suspension (200 mL) of thecompound prepared in Step 5 (2.5 g), followed by stirring for 21 hours.The reaction mixture is filtered through CELITE and the residue ispurified by silica gel column chromatography to obtain tert-butyl(3R)-3-[6-amino-8-oxo-7-(4-phenoxyphenyl)-7,8-dihydro-9H-purin-9-yl]pyrrolidine-1-carboxylate(1.3 g).

Step 7: At room temperature 4 N HCl/dioxane (13 mL) is added to amethanol (13 mL) suspension of the compound prepared in Step 6 (1.3 g2.76 mmol, 1.0 equivalent), and the mixture is stirred for 1 hour. Thesolvent is then distilled off to obtain(3R)-6-amino-9-pyrrolidin-3-yl-7-(4-phenoxyphenyl)-7,9-dihydro-8H-purin-8-onedihydrochloride (1.5 g).

Step 8: After 2-butylnoic acid (34 mg),1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) (78mg), 1-hydroxybenzotriazole (HOBt) (62 mg), and triethylamine (114 mL)are added to a solution of the compound prepared in Step 7 (100 mg) indimethyl formamide (3 mL), the mixture is stirred at room temperaturefor 3 hours. Water is added to the reaction mixture and extraction withethyl acetate is performed. The organic layer is washed with saturatedsodium carbonate solution and saturated aqueous sodium chloridesolution, then dried over anhydrous sodium sulfate, and the solvent isdistilled off. The residue is purified by thin layer chromatography(dichloromethane:methanol:28% ammonia water=90:10:1) to obtain6-amino-9-[(3R)-1-(2-butynoyl)-3-pyrrolidinyl]-7-(4-phenoxyphenyl)-7,9-dihydro-8H-purin-8-one(Formula (XXVIII-R)) (75 mg).

The hydrochloride salt of the compound of Formula (XXVIII-R) can beprepared as follows:6-amino-9-[(3R)-1-(2-butynoyl)-3-pyrrolidinyl]-7-(4-phenoxyphenyl)-7,9-dihydro-8H-purin-8-one(3.0 g) (which may be prepared as described above) is placed in a 300 mL3-neck pear-shaped flask, ethyl acetate (30 mL) and 1-propanol (4.5 mL)are added, and the external temperature is set at 70° C. (internaltemperature 61° C.). After it is confirmed that the compound prepared inStep 8 has dissolved completely, 10% HCl/methanol (3.5 mL) is added, andafter precipitation of crystals is confirmed, the crystals are ripenedby the following sequence: external temperature 70° C. for 30 min,external temperature 60° C. for 30 min, external temperature 50° C. for60 min, external temperature 40° C. for 30 min, room temperature for 30min, and an ice bath for 30 min. The resulting crystals are filtered,washed with ethyl acetate (6 mL), and dried under vacuum at 50° C. toobtain white crystals of6-amino-9-[(3R)-1-(2-butynoyl)-3-pyrrolidinyl]-7-(4-phenoxyphenyl)-7,9-dihydro-8H-purin-8-onehydrochloride (2.76 g).

In an embodiment, the BTK inhibitor is a compound selected from thestructures disclosed in U.S. Patent Application Publication No. US2014/0330015 A1, the disclosure of which is incorporated by referenceherein.

In an embodiment, the BTK inhibitor is a compound of Formula (B):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, wherein:

-   X—Y—Z is N—C—C and R² is present, or C—N—N and R² is absent;-   R¹ is a 3-8 membered, N-containing ring, wherein the N is    unsubstituted or substituted with R⁴;-   R² is H or lower alkyl, particularly methyl, ethyl, propyl or butyl;    or-   R¹ and R² together with the atoms to which they are attached, form a    4-8 membered ring, preferably a 5-6 membered ring, selected from    cycloalkyl, saturated or unsaturated heterocycle, aryl, and    heteroaryl rings unsubstituted or substituted with at least one    substituent L-R⁴;-   R³ is in each instance, independently halogen, alkyl, S-alkyl, CN,    or OR⁵;-   n is 1, 2, 3, or 4, preferably 1 or 2;-   L is a bond, NH, heteroalkyl, or heterocyclyl;-   R⁴ is COR′, CO₂R′, or SO₂R′, wherein R′ is substituted or    unsubstituted alkyl, substituted or unsubstituted alkenyl,    substituted or unsubstituted alkynyl;-   R⁵ is H or unsubstituted or substituted heteroalkyl, alkyl,    cycloalkyl, saturated or unsaturated heterocyclyl, aryl, or    heteroaryl.

In some embodiments, the BTK inhibitor is one of the followingparticular embodiments of Formula B:

-   X—Y—Z is C—N—N and R² is absent; and R¹ is 3-8 membered,    N-containing ring, N-substituted with R⁴;-   X—Y—Z is N—C—C and R² is present, R¹ is 3-8 membered, N-containing    ring, N-substituted with R⁴; and R² is H or lower alkyl;-   X—Y—Z is N—C—C and R² is present; and R¹ and R² together with the    atoms to which they are attached, form a 4-8 membered ring selected    from cycloalkyl, saturated or unsaturated heterocycle, aryl, and    heteroaryl rings unsubstituted or substituted with at least one    substituent L-R⁴, wherein preferred rings of R¹ and R² are    5-6-membered, particularly dihydropyrrole, tetrahydropyridine,    tetrahydroazepine, phenyl, or pyridine;-   X—Y—Z is N—C—C and R² is present; and R¹ and R² together with the    atoms to which they are attached, form a 5-6 membered ring,    preferably (a) phenyl substituted with a single -L-R⁴, or (b)    dihydropyrrole or tetrahydropyridine, N-substituted with a single    -L-R⁴ wherein L is bond;-   R¹ is piperidine or azaspiro[3.3]heptane, preferably N-substituted    with R⁴;-   R⁴ is COR′ or SO₂R′, particularly wherein R′ is substituted or    unsubstituted alkenyl, particularly substituted or unsubstituted    ethenyl; or-   R⁵ is unsubstituted or substituted alkyl or aryl, particularly    substituted or unsubstituted phenyl or methyl, such as    cyclopropyl-substituted methyl with or tetrabutyl-substituted    phenyl.

In some embodiments, the BTK inhibitor is one of the followingparticular embodiments of Formula B:

-   R¹ is piperidine or azaspiro[3.3]heptane, N-substituted with R⁴,    wherein R⁴ is H, COR′ or SO₂R′, and R′ is substituted or    unsubstituted alkenyl, particularly substituted or unsubstituted    ethenyl;-   R³ is —OR⁵, R⁵ is phenyl, and n is 1;-   R¹ and R², together with the atoms to which they are attached, form    a 5-6 membered ring, preferably (a) phenyl substituted with a single    -L-R⁴, or (b) dihydropyrrole or tetrahydropyridine, N-substituted    with a single -L-R⁴ wherein L is bond; R³ is —OR⁵; n is 1; R⁴ is    COR′, and R′ is ethenyl; and R⁵ is phenyl; and-   X—Y—Z is C—N—N and R² is absent; R¹ is piperidine, N-substituted    with R⁴; R³ is —OR⁵; n is 1; R⁴ is COR′, and R′ is unsubstituted or    substituted alkenyl, particularly ethenyl; and R⁵ is substituted or    unsubstituted aryl, particularly phenyl.

In an exemplary embodiment, the BTK inhibitor is a compound of Formula(B1), Formula (B1-2), or Formula (B1-3):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. Formula (B1-2) is also known as BGB-3111. Thepreparation of these compounds is described in International PatentApplication Publication No. WO 2014/173289 A1 and U.S. PatentApplication Publication No. US 2015/0005277 A1, the disclosure of whichis incorporated by reference herein.

In brief, the BTK inhibitor of Formula (B1) can be prepared by thefollowing procedure.

Step 1. Preparation of2-(hydroxy(4-phenoxyphenyl)methylene)malononitrile

A solution of 4-phenoxybenzoic acid (300 g, 1.4 mol) in SOCl₂ (1.2 L) isstirred at 80° C. under N₂ for 3 hours. The mixture is concentrated invacuum to give the intermediate (315 g) which is used for next stepwithout further purification.

To a solution of propanedinitrile (89.5 g, 1355 mmol) and DIEA (350 g,2710 mmol) in THF (800 mL) is dropwise a solution of the intermediate(315 g) in toluene (800 mL) at 0-5° C. over 2 hours. The resultantmixture is allowed to warm to RT and stirred for 16 hours. The reactionis quenched with water (2.0 L) and extracted with of EA (2.0 L×3). Thecombined organic layers are washed with 1000 mL of 3 N HCl aqueoussolution, brine (2.0 L×3), dried over Na₂SO₄ and concentrated to givethe crude product (330 g, 93%).

Step 2. Preparation of2-(Methoxy(4-phenoxyphenyl)methylene)malononitrile

A solution of 2-(hydroxy(4-phenoxyphenyl)methylene)malononitrile (50 g,190.8 mmol) in CH(OMe₃) (500 mL) is heated to 75° C. for 16 hours. Thenthe mixture is concentrated to a residue and washed with MeOH (50 mL) togive 25 g (47.5%) of 2-(methoxy(4-phenoxyphenyl)methylene)malononitrileas a yellow solid.

Step 3. Preparation of5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile

To a solution of 2-(methoxy(4-phenoxyphenyl)methylene)malononitrile (80g, 290 mmol) in ethanol (200 mL) is added hydrazine hydrate (20 mL). Themixture is stirred at RT for 16 hours then is concentrated to give thecrude product and washed with MeOH (30 mL) to afford 55 g (68.8%) of5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile as a off-whitesolid.

Step 4. Preparation of tert-butyl 3-(tosyloxy)piperidine-1-carboxylate

wherein “Boc” represents a tert-butyloxycarbonyl protecting group.

To a solution of tert-butyl 3-hydroxypiperidine-1-carboxylate (1.05 g,5.0 mmol) in pyridine (8 mL) is added TsCl (1.425 g, 7.5 mmol). Themixture is stirred at RT under N₂ for two days. The mixture isconcentrated and partitioned between 100 mL of EA and 100 mL of HCl (1N) aqueous solution. The organic layer is separated from aqueous layer,washed with saturated NaHCO₃ aqueous solution (100 mL×2), brine (100mL×3) and dried over Na₂SO₄. The organic layer is concentrated to afford1.1 g (60%) of tert-butyl 3-(tosyloxy)piperidine-1-carboxylate as acolorless oil.

Step 5. Preparation of tert-butyl3-(5-amino-4-cyano-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

To a solution of tert-butyl 3-(tosyloxy)piperidine-1-carboxylate (355mg, 1.0 mmol) and 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile(276 mg, 1.0 mmol) in 5 mL of DMF is added Cs₂CO₃ (650 mg, 2.0 mmol). Atosyloxy leaving group is employed in this reaction. The mixture isstirred at RT for 16 hours, 75° C. for 3 hours and 60° C. for 16 hours.The mixture is concentrated washed with brine (100 mL×3) and dried overNa₂SO₄. The material is concentrated and purified by chromatographycolumn on silica gel (eluted with petroleum ether/ethyl actate=3/1) toafford 60 mg (13%) of tert-butyl3-(5-amino-4-cyano-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylateas a yellow oil.

Step 6. Preparation of tert-butyl3-(5-amino-4-carbamoyl-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

To a solution of tert-butyl3-(5-amino-4-cyano-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(100 mg, 0.22 mmol) in DMSO (2 mL) and ethanol (2 mL) was added thesolution of NaOH (200 mg, 5 mmol) in water (1 mL) and H₂O₂(1 mL). Themixture is stirred at 60° C. for 15 min and concentrated to remove EtOH,after which 10 mL of water and 50 mL of ethyl acetate are added. Theorganic layer is separated from aqueous layer, washed with brine (30mL×3) and dried over Na₂SO₄. After concentration, 50 mg of residue isused directly in the next step, wherein 50 mg of residue is purified bypre-TLC (eluted with petroleum ether/ethyl actate=1/1) to afford 12 mg(30%) of tert-butyl3-(5-amino-4-carbamoyl-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylateas a white solid.

Step 7. Preparation of5-amino-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxamide

To a solution of tert-butyl3-(5-amino-4-carbamoyl-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(50 mg, 0.11 mmol) in ethyl acetate (1 mL) is added concentrated HCl(0.75 mL). The mixture is stirred at RT for 1 hour. Then saturatedNaHCO₃ is added until pH >7, followed by ethyl acetate (50 mL). Theorganic layer is separated from aqueous layer, washed with brine (50mL×3) and dried over Na₂SO₄. The resulting product is concentrated andpurified by Pre-TLC (eluted with dichloromethane/MeOH/NH₃—H₂O=5/1/0.01)to afford 10 mg (25%) of5-amino-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxamideas a white solid.

Step 8. Preparation of1-(1-acryloylpiperidin-3-yl)-5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide

To a solution of5-amino-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxamide(63 mg, 0.17 mmol) in dichloromethane (4 mL) is added pyridine (27 mg,0.34 mmol). Then a solution of acryloyl chloride (12 mg, 0.17 mmol) indichloromethane (1 mL) is added dropwise. After stirring at RT for 4hours, the mixture is partitioned between 100 mL of dichloromethane and100 mL of brine. The organic layer is separated from aqueous layer,washed with brine (100 mL×2) and dried over Na₂SO₄. The material isconcentrated and purified by Pre-TLC (eluted withdichloromethane/MeOH=10/1) to afford 4 mg (5.5%) of1-(1-acryloylpiperidin-3-yl)-5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamideas a white solid.

The enantiomers of Formula (B1) provided by the procedure above may beprepared from 5-amino-3-(phenoxyphenyl)-1H-pyrazole-4-carbonitrile and(S)-tert-butyl 3-hydroxypiperidine-1-carboxylate using a similarprocedure (step 4 to 8) for Formula (B1-2), or from (R)-tert-butyl3-hydroxypiperidine-1-carboxylate using a similar procedure (step 4 to8) for Formula (B1-3). Under appropriate conditions recognized by one ofordinary skill in the art, a racemic mixture of Formula (B1) may beseparated by chiral HPLC, the crystallization of chiral salts, or othermeans described above to yield Formula (B1-2) and Formula (B1-3) of highenantiomeric purity.

In an embodiment, the BTK inhibitor is a compound selected from thestructures disclosed in U.S. Patent Application Publication No. US2015/0005277A1, the disclosure of which is incorporated by referenceherein.

Other BTK inhibitors suitable for use in the described combination witha JAK-2 inhibitor or a PI3K inhibitor, the PI3K inhibitor beingpreferably selected from the group consisting of a PI3K-γ inhibitor, aPI3K-δ inhibitor, and a PI3K-γ,δ inhibitor, also include, but are notlimited to, those described in, for example, International PatentApplication Publication Nos. WO 2013/010868, WO 2012/158843, WO2012/135944, WO 2012/135937, U.S. Patent Application Publication No.2011/0177011, and U.S. Pat. Nos. 8,501,751, 8,476,284, 8,008,309,7,960,396, 7,825,118, 7,732,454, 7,514,444, 7,459,554, 7,405,295, and7,393,848, the disclosures of each of which are incorporated herein byreference.

JAK-2 Inhibitors

The JAK-2 inhibitor may be any JAK-2 inhibitor known in the art. Inparticular, it is one of the JAK-2 inhibitors described in more detailin the following paragraphs. In preferred embodiments, the compositionsdescribed herein provide a combination of a JAK-2 inhibitor with a BTKinhibitor, or methods of using a combination of a JAK-2 inhibitor with aBTK inhibitor. In some embodiments, the JAK-2 inhibitors provided hereinare selective for JAK-2, in that the compounds bind or interact withJAK-2 at substantially lower concentrations than they bind or interactwith other JAK receptors, including the JAK-3 receptor. In certainembodiments, the compounds bind to the JAK-3 receptor at a bindingconstant that is at least about a 2-fold higher concentration, about a3-fold higher concentration, about a 5-fold higher concentration, abouta 10-fold higher concentration, about a 20-fold higher concentration,about a 30-fold higher concentration, about a 50-fold higherconcentration, about a 100-fold higher concentration, about a 200-foldhigher concentration, about a 300-fold higher concentration, or about a500-fold higher concentration than to the JAK-2 receptor.

In an embodiment, the JAK-2 inhibitor is a compound of Formula (XXIX):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, wherein:

-   A¹ and A² are independently selected from C and N;-   T, U, and V are independently selected from O, S, N, CR⁵, and NR⁶;-   wherein the 5-membered ring formed by A¹, A², U, T, and V is    aromatic;-   X is N or CR⁴;-   Y is C₁₋₈ alkylene, C₂₋₈ alkenylene, C₂₋₈ alkynylene,    (CR¹¹R¹²)_(p)—(C₃₋₁₀ cycloalkylene)-(CR¹¹R¹²)_(q),    (CR¹¹R¹²)_(p)-(arylene)-(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)—(C₁₋₁₀    heterocycloalkylene)-(CR¹¹R¹²)_(q),    (CR¹¹R¹²)_(p)-(heteroarylene)-(CR¹¹R¹²)_(q),    (CR¹¹R¹²)O(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)S(CR¹¹R¹²)_(q),    (CR¹¹R¹²)_(p)C(O)(CR¹¹R¹²)_(q),    (CR¹¹R¹²)_(p)C(O)NR^(c)(CR¹¹R¹²)_(q),    (CR¹¹R¹²)_(p)C(O)O(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)OC(O)(CR¹¹R¹²)_(q),    (CR¹¹R¹²)_(p)OC(O)NR^(c)(CR¹¹R¹²)_(q),    (CR¹¹R¹²)_(p)NR^(c)(CR¹¹R¹²)_(q),    (CR¹¹R¹²)_(p)NR^(c)C(O)NR^(d)(CR¹¹R¹²)_(q),    (CR¹¹R¹²)_(p)S(O)(CR¹¹R¹²)_(q),    (CR¹¹R¹²)_(p)S(O)NR^(c)(CR¹¹R¹²)_(q),    (CR¹¹R¹²)_(p)S(O)₂(CR¹¹R¹²)_(q), or    (CR¹¹R¹²)_(p)S(O)₂NR^(c)(CR¹¹R¹²)_(q), wherein said C₁₋₈ alkylene,    C₂₋₈ alkenylene, C₂₋₈ alkynylene, cycloalkylene, arylene,    heterocycloalkylene, or heteroarylene, is optionally substituted    with 1, 2, or 3 substituents independently selected from    -D¹-D²-D³-D⁴;-   Z is H, halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄    haloalkyl, halosulfanyl, C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl,    ═C—R^(i), ═N—R^(i), Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),    C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),    NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),    NR^(c)C(O)OR^(a), C(═NR^(i))NR^(c)R^(d),    NR^(c)C(═NR^(i))NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),    NR^(c)S(O)₂R^(b), C(═NOH)R^(b), C(═NO(C₁₋₆ alkyl)R^(b), and    S(O)₂NR^(c)R^(d), wherein said C₁₋₈ alkyl, C₂₋₈ alkenyl, or C₂₋₈    alkynyl, is optionally substituted with 1, 2, 3, 4, 5, or 6    substituents independently selected from halo, C₁₋₄ alkyl, C₂₋₄    alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄    hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a),    C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),    OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),    NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a) C(═NR^(i))NR^(c)R^(d),    NR^(c)C(═NR^(i))NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),    NR^(c)S(O)₂R^(b), C(═NOH)R^(b), C(═NO(C₁₋₆ alkyl)R^(b), and    S(O)₂NR^(c)R^(d);-   wherein when Z is H, n is 1;-   or the —(Y)_(n)—Z moiety is taken together with i) A² to which the    moiety is attached, ii) R⁵ or R⁶ of either T or V, and iii) the C or    N atom to which the R⁵ or R⁶ of either T or V is attached to form a    4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl    ring fused to the 5-membered ring formed by A¹, A², U, T, and V,    wherein said 4- to 20-membered aryl, cycloalkyl, heteroaryl, or    heterocycloalkyl ring is optionally substituted by 1, 2, 3, 4, or 5    substituents independently selected from -(W)_(m)-Q;-   W is C₁₋₈ alkylenyl, C₂₋₈ alkenylenyl, C₂₋₈ alkynylenyl, O, S, C(O),    C(O)NR^(c′), C(O)O, OC(O), OC(O)NR^(c′), NR^(c′),    NR^(c′)C(O)NR^(d′), S(O), S(O)NR^(c′), S(O)₂, or S(O)₂NR^(c′);-   Q is H, halo, CN, NO₂, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈    haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, or    heterocycloalkyl, wherein said C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈    alkynyl, C₁₋₈ haloalkyl, aryl, cycloalkyl, heteroaryl, or    heterocycloalkyl is optionally substituted with 1, 2, 3 or 4    substituents independently selected from halo, C₁₋₄ alkyl, C₂₋₄    alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄    hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy², CN, NO₂, OR^(a′), SR^(a′),    C(O)R^(b′), C(O)NR^(c′)R^(d′), C(O)OR^(a′), OC(O)R^(b′),    OC(O)NR^(c′)R^(d′), NR^(c′)R^(d′), NR^(c′)C(O)R^(b′),    NR^(c′)C(O)NR^(c′)R^(d′), NR^(c′)C(O)OR^(a′), S(O)R^(b′),    S(O)NR^(c′)R^(d′), S(O)₂R^(b′), NR^(c′)S(O)₂R^(b′), and    S(O)₂NR^(c′)R^(d′);-   Cy¹ and Cy² are independently selected from aryl, heteroaryl,    cycloalkyl, and heterocycloalkyl, each optionally substituted by 1,    2, 3, 4 or 5 substituents independently selected from halo, C₁₋₄    alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, halosulfanyl,    C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, CN, NO₂, OR^(a″), SR^(a″),    C(O)R^(b″), C(O)NR^(c″)R^(d″), C(O)OR^(a″),    OC(O)R^(b″)OC(O)NR^(c″)R^(d″), NR^(c″)R^(d″), NR^(c″)C(O)R^(b″),    NR^(c″)C(O)OR^(a″), NR^(c″)S(O)R^(b″), NR^(c″)S(O)₂R^(b″),    S(O)R^(b″), S(O)NR^(c″)R^(d″), S(O)₂R^(b″), and S(O)₂NR^(c″)R^(d″);-   R¹, R², R³, and R⁴ are independently selected from H, halo, C₁₋₄    alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, halosulfanyl,    aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR⁷, SR⁷,    C(O)R⁸, C(O)NR⁹R¹⁰, C(O)OR⁷OC(O)R⁸, OC(O)NR⁹R¹⁰, NR⁹R¹¹, NR⁹C(O)R⁸,    NR^(c)C(O)OR⁷, S(O)R⁸, S(O)NR⁹R¹⁰, S(O)₂R⁸, NR⁹S(O)₂R⁸, and    S(O)₂NR⁹R¹⁰;-   R⁵ is H, halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄    haloalkyl, halosulfanyl, CN, NO₂, OR⁷, SR⁷, C(O)R⁸, C(O)NR⁹R¹⁰,    C(O)OR⁷, OC(O)R⁸, OC(O)NR⁹R¹⁰, NR⁹R¹⁰, NR⁹C(O)R⁸, NR⁹C(O)OR⁷,    S(O)R⁸, S(O)NR⁹R¹⁰, S(O)₂R⁸, NR⁹S(O)₂R⁸, or S(O)₂NR⁹R¹⁰;-   R⁶ is H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,    OR⁷, C(O)R⁸, C(O)NR⁹R¹⁰, C(O)OR⁷, S(O)R⁸, S(O)NR⁹R¹⁰, S(O)₂R⁸, or    S(O)₂NR⁹R¹⁰;-   R⁷ is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,    heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl;-   R⁸ is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,    heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl;-   R⁹ and R¹⁰ are independently selected from H, C₁₋₁₀ alkyl, C₁₋₆    haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkylcarbonyl,    arylcarbonyl, C₁₋₆ alkylsulfonyl, arylsulfonyl, aryl, heteroaryl,    cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,    cycloalkylalkyl and heterocycloalkylalkyl;-   or R⁹ and R¹⁰ together with the N atom to which they are attached    form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;-   R¹¹ and R¹² are independently selected from H and -E¹-E²-E³-E⁴;-   D¹ and E¹ are independently absent or independently selected from    C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, arylene,    cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each    of the C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, arylene,    cycloalkylene, heteroarylene, and heterocycloalkylene is optionally    substituted by 1, 2 or 3 substituents independently selected from    halo, CN, NO₂, N₃, SCN, OH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₈    alkoxyalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylamino,    and C₂₋₈ dialkylamino;-   D² and E² are independently absent or independently selected from    C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, (C₁₋₆    alkylene)_(r)-O—(C₁₋₆ alkylene)_(s), (C₁₋₆ alkylene)_(r)-S—(C₁₋₆    alkylene)_(s), (C₁₋₆ alkylene)_(s), —NR^(e)—(C₁₋₆ alkylene)_(s),    (C₁₋₆ alkylene)_(r)-CO—(C₁₋₆ alkylene)_(s), (C₁₋₆    alkylene)_(r)-COO—(C₁₋₆ alkylene)_(s), (C₁₋₆    alkylene)_(r)-CONR^(e)—(C₁₋₆ alkylene)_(s), (C₁₋₆    alkylene)_(r)-SO—(C₁₋₆ alkylene)_(s), (C₁₋₆ alkylene)_(r)-SO₂—(C₁₋₆    alkylene)_(s), (C₁₋₆ alkylene)_(r)-SONR^(c)—(C₁₋₆ alkylene)_(s), and    (C₁₋₆ alkylene)_(r)-NR^(e)CONR^(f)—(C₁₋₆ alkylene)_(s), wherein each    of the C₁₋₆ alkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene is    optionally substituted by 1, 2 or 3 substituents independently    selected from halo, CN, NO₂, N₃, SCN, OH, C₁₋₆ alkyl, C₁₋₆    haloalkyl, C₂₋₈ alkoxyalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino,    C₁₋₆ alkylamino, and C₂₋₈ dialkylamino;-   D³ and E³ are independently absent or independently selected from    C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, arylene,    cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each    of the C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, arylene,    cycloalkylene, heteroarylene, and heterocycloalkylene is optionally    substituted by 1, 2 or 3 substituents independently selected from    halo, CN, NO₂, N₃, SCN, OH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₈    alkoxyalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylamino,    and C₂₋₈ dialkylamino;-   D⁴ and E⁴ are independently selected from H, halo, C₁₋₄ alkyl, C₂₋₄    alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄    hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a),    C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),    OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),    NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), C(═NR^(i))NR^(c)R^(d),    NR^(c)C(═NR^(i))NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),    NR^(c)S(O)₂R^(b), C(═NOH)R^(b), C(═NO(C₁₋₆ alkyl)R^(b), and    S(O)₂NR^(c)R^(d), wherein said C₁₋₈ alkyl, C₂₋₈ alkenyl, or C₂₋₈    alkynyl, is optionally substituted with 1, 2, 3, 4, 5, or 6    substituents independently selected from halo, C₁₋₄ alkyl, C₂₋₄    alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄    hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a),    C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),    OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),    NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), —C(═NR^(i))NR^(c)R^(d),    NR^(c)C(═NR^(i))NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),    NR^(c)S(O)₂R^(b), C(═NOH)R^(b), C(═NO(C₁₋₆ alkyl))R^(b), and    S(O)₂NR^(c)R^(d);-   R^(a) is H, Cy¹, —(C₁₋₆ alkyl)-Cy¹, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆    alkenyl, or C₂₋₆ alkynyl is optionally substituted with 1, 2, or 3    substituents independently selected from OH, CN, amino, halo, C₁₋₆    alkyl, C₁₋₆ haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl,    heteroarylalkyl, cycloalkyl and heterocycloalkyl;-   R^(b) is H, Cy¹, —(C₁₋₆ alkyl)-Cy, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆    alkenyl, or C₂₋₆ alkynyl is optionally substituted with 1, 2, or 3    substituents independently selected from OH, CN, amino, halo, C₁₋₆    alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl, halosulfanyl, aryl,    arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and    heterocycloalkyl;-   R^(a′) and R^(a″) are independently selected from H, C₁₋₆ alkyl,    C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,    heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,    cycloalkylalkyl and heterocycloalkylalkyl, wherein said C₁₋₆ alkyl,    C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,    heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,    cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted    with 1, 2, or 3 substituents independently selected from OH, CN,    amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halosulfanyl, aryl,    arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and    heterocycloalkyl;-   R^(b′) and R^(b″) are independently selected from H, C₁₋₆ alkyl,    C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,    heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,    cycloalkylalkyl and heterocycloalkylalkyl, wherein said C₁₋₆ alkyl,    C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,    heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,    cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted    with 1, 2, or 3 substituents independently selected from OH, CN,    amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl,    halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,    cycloalkyl and heterocycloalkyl;-   R^(c) and R^(d) are independently selected from H, Cy¹, —(C₁₋₆    alkyl)-Cy¹, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, or C₂₋₆    alkynyl, is optionally substituted with 1, 2, or 3 substituents    independently selected from Cy¹, —(C₁₋₆ alkyl)-Cy¹, OH, CN, amino,    halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl, and halosulfanyl;-   or R^(c) and R^(d) together with the N atom to which they are    attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group    optionally substituted with 1, 2, or 3 substituents independently    selected from Cy¹, —(C₁₋₆ alkyl)-Cy¹, OH, CN, amino, halo, C₁₋₆    alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl, and halosulfanyl;-   R^(c′) and R^(d′) are independently selected from H, C₁₋₁₀ alkyl,    C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl,    cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,    cycloalkylalkyl and heterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl,    C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl,    cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,    cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted    with 1, 2, or 3 substituents independently selected from OH, CN,    amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl,    halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,    cycloalkyl and heterocycloalkyl;-   or R^(c′) and R^(d′) together with the N atom to which they are    attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group    optionally substituted with 1, 2, or 3 substituents independently    selected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆    haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl,    heteroarylalkyl, cycloalkyl and heterocycloalkyl;-   R^(c″) and R^(d″) are independently selected from H, C₁₋₁₀ alkyl,    C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl,    cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,    cycloalkylalkyl and heterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl,    C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl,    cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,    cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted    with 1, 2, or 3 substituents independently selected from OH, CN,    amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halosulfanyl, C₁₋₆    haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl    and heterocycloalkyl;-   or R^(c″) and R^(d″) together with the N atom to which they are    attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group    optionally substituted with 1, 2, or 3 substituents independently    selected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆    haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl,    heteroarylalkyl, cycloalkyl and heterocycloalkyl;-   R^(i) is H, CN, NO₂, or C₁₋₆ alkyl;-   R^(e) and R are independently selected from H and C₁₋₆ alkyl;-   R^(i) is H, CN, or NO₂;-   m is 0 or 1;-   n is 0 or 1;-   p is 0, 1, 2, 3, 4, 5, or 6;-   q is 0, 1, 2, 3, 4, 5 or 6;-   r is 0 or 1; and-   s is 0 or 1.

In some embodiments, when X is N, n is 1, and the moiety formed by A¹,A², U, T, V, and —(Y)_(n)—Z has the formula:

then Y is other than (CR¹¹R¹²)_(p)C(O)NR^(c)(CR¹¹R¹²)_(q).

In some embodiments, when X is N, the 5-membered ring formed by A¹, A²,U, T, and V is other than pyrrolyl.

In some embodiments, when X is CH, n is 1, and the moiety formed by A¹,A², U, T, V, and —(Y)_(n)—Z has the formula:

then —(Y)_(n)—Z is other than COOH.

In some embodiments, when X is CH or C-halo, R¹, R², and R³ are each H,n is 1, and the moiety formed by A¹, A², U, T, V, and —(Y)_(n)—Z has theformula:

then Y is other than (CR¹¹R¹²)_(p)C(O)NR^(c)(CR¹¹R¹²)_(q) or(CR¹¹R¹²)_(p)C(O)(CR¹¹R¹²)_(q).

In some embodiments, when X is CH or C-halo, R¹, R², and R³ are each H,n is 0, and the moiety formed by A¹, A², U, T, V, and —(Y)_(n)—Z has theformula:

then Z is other than CN, halo, or C₁₋₄ alkyl.

In some embodiments, when X is CH or C-halo, R¹, R², and R³ are each H,n is 1, and the moiety formed by A¹, A², U, T, V, and —(Y)_(n)—Z has theformula:

then Y is other than (CR¹¹R¹²)_(p)C(O)NR^(c)(CR¹¹R¹²)_(q) or(CR¹¹R¹²)_(p)C(O)(CR¹¹R¹²)_(q).

In some embodiments, when X is CH or C-halo, R¹, R², and R³ are each H,n is 1, and the moiety formed by A¹, A², U, T, V, and —(Y)_(n)—Z has theformula:

then Y is other than (CR¹¹R¹²)_(p)NR^(c)(CR¹¹R¹²)_(q).

In some embodiments, when X is CH or C-halo and R¹, R², and R³ are eachH, then the moiety formed by A¹, A², U, T, V, and —(Y)_(n)—Z has aformula other than:

In some embodiments:

-   Z is H, halo, CN, NO₂, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈    haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl,    wherein said C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ haloalkyl,    aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally    substituted with 1, 2, 3, 4, 5, or 6 substituents independently    selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄    haloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂, OR^(a),    SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),    OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),    NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), C(═NR^(i))NR^(c)R^(d),    NR^(c)C(═NR^(i))NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),    NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d);-   Q is H, halo, CN, NO₂, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈    haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl,    wherein said C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ haloalkyl,    aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally    substituted with 1, 2, 3 or 4 substituents independently selected    from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,    C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy², CN, NO₂, OR^(a′), SR^(a′),    C(O)R^(b′), C(O)NR^(c′)R^(d′), C(O)OR^(a′), OC(O)R^(b′),    OC(O)NR^(c′)R^(d′), NR^(c′)R^(d′), NR^(c′)C(O)R^(b′),    NR^(c′)C(O)NR^(c′)R^(d′), NR^(c′)C(O)OR^(a′), S(O)R^(b′),    S(O)NR^(c′)R^(d′), S(O)₂R^(b′), NR^(c′)S(O)₂R^(b′), and    S(O)₂NR^(c′)R^(d′);-   Cy¹ and Cy¹ are independently selected from aryl, heteroaryl,    cycloalkyl, and heterocycloalkyl, each optionally substituted by 1,    2, 3, 4 or 5 substituents independently selected from halo, C₁₋₄    alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄    hydroxyalkyl, C₁₋₄ cyanoalkyl, CN, NO₂, OR^(a″), SR^(a″),    C(O)R^(b″), C(O)NR^(c″)R^(d″), C(O)OR^(a″), OC(O)R^(b″),    OC(O)NR^(c″)R^(d″), NR^(c″)R^(d″), NR^(c″)C(O)R^(b″),    NR^(c″)C(O)OR^(a″), NR^(c″)S(O)R^(b″), NR^(c″)S(O)₂R^(b″),    S(O)R^(b″), S(O)NR^(c″)R^(d″), S(O)₂R^(b″), and S(O)₂NR^(c″)R^(d″);-   R¹, R², R³, and R⁴ are independently selected from H, halo, C₁₋₄    alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl, cycloalkyl,    heteroaryl, heterocycloalkyl, CN, NO₂, OR⁷, SR⁷, C(O)R⁸, C(O)NR⁹R¹⁰,    C(O)OR⁷OC(O)R⁸, OC(O)NR⁹R¹⁰, NR⁹R¹⁰, NR⁹C(O)R⁸, NR⁹C(O)OR⁷, S(O)R⁸,    S(O)NR⁹R¹⁰, S(O)₂R⁸, NR⁹S(O)₂R⁸, and S(O)₂NR⁹R¹⁰;-   R⁵ is H, halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄    haloalkyl, CN, NO₂, OR⁷, SR⁷, C(O)R⁸, C(O)NR⁹R¹⁰, C(O)OR⁷, OC(O)R⁸,    OC(O)NR⁹R¹⁰, NR⁹R¹⁰, NR⁹C(O)R⁸, NR⁹C(O)OR⁷, S(O)R⁸, S(O)NR⁹R¹⁰,    S(O)₂R⁸, NR⁹S(O)₂R⁸, or S(O)₂NR⁹R¹⁰;-   R⁶ is H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,    OR⁷, C(O)R⁸, C(O)NR⁹R¹⁰, C(O)OR⁷, S(O)R⁸, S(O)NR⁹R¹⁰, S(O)₂R⁸, or    S(O)₂NR⁹R¹⁰;-   R⁷ is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,    heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl;-   R⁸ is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,    heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl;-   R⁹ and R¹⁰ are independently selected from H, C₁₋₁₀ alkyl, C₁₋₆    haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkylcarbonyl,    arylcarbonyl, C₁₋₆ alkylsulfonyl, arylsulfonyl, aryl, heteroaryl,    cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,    cycloalkylalkyl and heterocycloalkylalkyl;-   or R⁹ and R¹⁰ together with the N atom to which they are attached    form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;-   R¹¹ and R¹² are independently selected from H, halo, OH, CN, C₁₋₄    alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄    hydroxyalkyl, C₁₋₄ cyanoalkyl, aryl, heteroaryl, cycloalkyl, and    heterocycloalkyl;-   R^(a), R^(a′), and R^(a″) are independently selected from H, C₁₋₆    alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,    heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,    cycloalkylalkyl and heterocycloalkylalkyl, wherein said C₁₋₆ alkyl,    C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,    heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,    cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted    with 1, 2, or 3 substituents independently selected from OH, CN,    amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl, arylalkyl,    heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;-   R^(b), R^(b′) and R^(b″) are independently selected from H, C₁₋₆    alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,    heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,    cycloalkylalkyl and heterocycloalkylalkyl, wherein said C₁₋₆ alkyl,    C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,    heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,    cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted    with 1, 2, or 3 substituents independently selected from OH, CN,    amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl, aryl,    arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and    heterocycloalkyl;-   R^(c) and R^(d) are independently selected from H, C₁₋₁₀ alkyl, C₁₋₆    haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,    heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and    heterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl,    C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,    heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or    heterocycloalkylalkyl is optionally substituted with 1, 2, or 3    substituents independently selected from OH, CN, amino, halo, C₁₋₆    alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl,    heteroarylalkyl, cycloalkyl or heterocycloalkyl;-   or R^(c) and R^(d) together with the N atom to which they are    attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group    optionally substituted with 1, 2, or 3 substituents independently    selected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆    haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl    and heterocycloalkyl;-   R^(c′) and R^(d′) are independently selected from H, C₁₋₁₀ alkyl,    C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl,    cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,    cycloalkylalkyl and heterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl,    C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl,    cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,    cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted    with 1, 2, or 3 substituents independently selected from OH, CN,    amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl, aryl,    arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and    heterocycloalkyl;-   or R^(c′) and R^(d′) together with the N atom to which they are    attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group    optionally substituted with 1, 2, or 3 substituents independently    selected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆    haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl    and heterocycloalkyl;-   R^(c″) and R^(d″) are independently selected from H, C₁₋₁₀ alkyl,    C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl,    cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,    cycloalkylalkyl and heterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl,    C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl,    cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,    cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted    with 1, 2, or 3 substituents independently selected from OH, CN,    amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl, aryl,    arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and    heterocycloalkyl;-   or R^(c″) and R^(d″) together with the N atom to which they are    attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group    optionally substituted with 1, 2, or 3 substituents independently    selected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆    haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl    and heterocycloalkyl.

In some embodiments, X is N.

In some embodiments, X is CR⁴.

In some embodiments, A¹ is C.

In some embodiments, A¹ is N.

In some embodiments, A² is C.

In some embodiments, A² is N.

In some embodiments, at least one of A¹, A², U, T, and V is N.

In some embodiments, the 5-membered ring formed by A¹, A², U, T, and Vis pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, or oxadiazolyl.

In some embodiments, the 5-membered ring formed by A¹, A², U, T, and Vis selected from:

wherein:a designates the site of attachment of moiety —(Y)_(n)—Z;b designates the site of attachment to the core moiety:

andc and c′ designate the two site of attachment of the fused 4- to20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring.

In some embodiments, the 5-membered ring formed by A¹, A², U, T, and Vis:

wherein:a designates the site of attachment of moiety —(Y)_(n)—Z;b designates the site of attachment to the core moiety.

andc and c′ designate the two sites of attachment of the fused 4- to20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring.

In some embodiments, the 5-membered ring formed by A¹, A², U, T, and Vis selected from:

wherein:a designates the site of attachment of moiety —(Y)_(n)—Z;b designates the site of attachment to the core moiety:

andc and c′ designate the two sites of attachment of the fused 4- to20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring.

In some embodiments, the 5-membered ring formed by A¹, A², U, T, and Vis selected from:

wherein:a designates the site of attachment of moiety —(Y)_(n)—Z;b designates the site of attachment to the core moiety:

In some embodiments, the 5-membered ring formed by A¹, A², U, T, and Vis selected from:

wherein:a designates the site of attachment of moiety —(Y)_(n)—Z;b designates the site of attachment to the core moiety:

In some embodiments, the 5-membered ring formed by A¹, A², U, T, and Vis selected from:

wherein:a designates the site of attachment of moiety —(Y)_(n)—Z;b designates the site of attachment to the core moiety:

In some embodiments, n is 0.

In some embodiments, n is 1.

In some embodiments, n is 1 and Y is C₁₋₈ alkylene, C₂₋₈ alkenylene,(CR¹¹R¹²)_(p)C(O)(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)C(O)NR^(c)(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)C(O)O(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)OC(O)(CR¹¹R¹²)_(q),wherein said C₁₋₈ alkylene or C₂₋₈ alkenylene, is optionally substitutedwith 1, 2, or 3 halo, OH, CN, amino, C₁₋₄ alkylamino, or C₂₋₈dialkylamino.

In some embodiments, n is 1 and Y is C₁₋₈ alkylene,(CR¹¹R¹²)_(p)C(O)(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)C(O)NR^(c)(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)C(O)O(CR¹¹R¹²)_(q), wherein said C₁₋₈ alkylene isoptionally substituted with 1, 2, or 3 halo, OH, CN, amino, C₁₋₄alkylamino, or C₂₋₈ dialkylamino.

In some embodiments, n is 1 and Y is C₁₋₈ alkylene optionallysubstituted with 1, 2, or 3 halo, OH, CN, amino, C₁₋₄ alkylamino, orC₂₋₈ dialkylamino.

In some embodiments, n is 1 and Y is ethylene optionally substitutedwith 1, 2, or 3 halo, OH, CN, amino, C₁₋₄ alkylamino, or C₂₋₈dialkylamino.

In some embodiments, n is 1 and Y is (CR¹¹R¹²)_(p)C(O)(CR¹¹R¹²)_(q)(CR¹¹R¹²)_(p)C(O)NR^(c)(CR¹¹R¹²)_(q), or (CR¹¹R¹²)_(p)C(O)O(CR¹¹R¹²)_(q).

In some embodiments, Y is C₁₋₈ alkylene, C₂₋₈ alkenylene, C₂₋₈alkynylene, (CR¹¹R¹²)_(p)—(C₃₋₁₀ cycloalkylene)-(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)-(arylene)-(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)—(C₁₋₁₀heterocycloalkylene)-(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)-(heteroarylene)-(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)O(CR¹¹R¹²)_(q), or (CR¹¹R¹²)S(CR¹¹R¹²)_(q), wherein saidC₁₋₈ alkylene, C₂₋₈ alkenylene, C₂₋₈ alkynylene, cycloalkylene, arylene,heterocycloalkylene, or heteroarylene, is optionally substituted with 1,2, or 3 substituents independently selected from -D¹-D²-D³-D⁴.

In some embodiments, Y is C₁₋₈ alkylene, C₂₋₈ alkenylene, C₂₋₈alkynylene, (CR¹¹R¹²)_(p)—(C₃₋₁₀ cycloalkylene)-(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)-(arylene)-(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)—(C₁₋₁₀heterocycloalkylene)-(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)-(heteroarylene)-(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)O(CR¹¹R¹²)_(q), or (CR¹¹R¹²)_(p)S(CR¹¹R¹²)_(q), whereinsaid C₁₋₈ alkylene, C₂₋₈ alkenylene, C₂₋₈ alkynylene, cycloalkylene,arylene, heterocycloalkylene, or heteroarylene, is optionallysubstituted with 1, 2, or 3 substituents independently selected from D⁴.

In some embodiments, Y is C₁₋₈ alkylene, C₂₋₈ alkenylene, C₂₋₈alkynylene, or (CR¹¹R¹²)_(p) (C₃₋₁₀ cycloalkylene)-(CR¹¹R¹²)_(q),wherein said C₁₋₈ alkylene, C₂₋₈ alkenylene, C₂₋₈ alkynylene, orcycloalkylene, is optionally substituted with 1, 2, or 3 substituentsindependently selected from -D¹-D²-D³-D⁴.

In some embodiments, Y is C₁₋₈ alkylene, C₂₋₈ alkenylene, C₂₋₈alkynylene, or (CR¹¹R¹²)_(p)—(C₃₋₁₀ cycloalkylene)-(CR¹¹R¹²)_(q),wherein said C₁₋₈ alkylene, C₂₋₈ alkenylene, C₂₋₈ alkynylene, orcycloalkylene, is optionally substituted with 1, 2, or 3 substituentsindependently selected from D⁴.

In some embodiments, Y is C₁₋₈ alkylene, C₂₋₈ alkenylene, or C₂₋₈alkynylene, each optionally substituted with 1, 2, or 3 substituentsindependently selected from -D¹-D²-D³-D⁴

In some embodiments, Y is C₁₋₈ alkylene optionally substituted with 1,2, or 3 substituents independently selected from -D¹-D²-D³-D⁴.

In some embodiments, Y is C₁₋₈ alkylene optionally substituted with 1,2, or 3 substituents independently selected from D⁴.

In some embodiments, Y is C₁₋₈ alkylene, C₂₋₈ alkenylene, C₂₋₈alkynylene, (CR¹¹R¹²)_(p)O—(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)S(CR¹¹R¹²)_(q),(CR¹¹R¹²)C(O)(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)C(O)NR^(c)(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)C(O)O(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)OC(O)(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)OC(O)NR^(c)(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)NR^(c)(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)NR^(c)C(O)NR^(d)(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)S(O)(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)S(O)NR^(c)(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)S(O)₂(CR¹¹R¹²)_(q), or(CR¹¹R¹²)_(p)S(O)₂NR^(c)(CR¹¹R¹²)_(q), wherein said C₁₋₈ alkylene, C₂₋₈alkenylene, C₂₋₈ alkynylene is optionally substituted with 1, 2, or 3substituents independently selected from halo, OH, CN, amino, C₁₋₄alkylamino, and C₂₋₈ dialkylamino.

In some embodiments, Y is C₁₋₈ alkylene, C₂₋₈ alkenylene, C₂₋₈alkynylene, (CR¹¹R¹²)_(p)—(C₃₋₁₀ cycloalkylene)-(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)-(arylene)-(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)—(C₁₋₁₀heterocycloalkylene)-(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)-(heteroarylene)-(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)O(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)S(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)C(O)(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)C(O)NR^(c)(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)C(O)O(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)OC(O)(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)OC(O)NR^(c)(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)NR^(c)(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)NR^(c)C(O)NR^(d)(CR¹¹R¹²)_(q), (CR¹¹R¹²)S(O)(CR¹¹R¹²)_(q),(CR¹¹R¹²)_(p)S(O)NR^(c)(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)S(O)₂(CR¹¹R¹²)_(q),or (CR¹¹R¹²)_(p)S(O)₂NR(CR¹¹R¹²)_(q), wherein said C₁₋₈ alkylene, C₂₋₈alkenylene, C₂₋₈ alkynylene, cycloalkylene, arylene,heterocycloalkylene, or heteroarylene, is optionally substituted with 1,2, or 3 substituents independently selected from halo, OH, CN, amino,C₁₋₄ alkylamino, and C₂₋₈ dialkylamino.

In some embodiments, p is 0.

In some embodiments, p is 1.

In some embodiments, p is 2.

In some embodiments, q is 0.

In some embodiments, q is 1.

In some embodiments, q is 2.

In some embodiments, one of p and q is 0 and the other of p and q is 1,2, or 3.

In some embodiments, Z is H, halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄ hydroxyalkyl, C₁₋₄cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), C(═NR^(i))NR^(c)R^(d),NR^(c)C(═NR^(i))NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),NR^(c)S(O)₂R^(b), C(═NOH)R^(b), C(═NO(C₁₋₆ alkyl)R^(b), andS(O)₂NR^(c)R^(d), wherein said C₁₋₈ alkyl, C₂₋₈ alkenyl, or C₂₋₈alkynyl, is optionally substituted with 1, 2, 3, 4, 5, or 6 substituentsindependently selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄ hydroxyalkyl, C₁₋₄cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), C(═NR^(i))NR^(c)R^(d),NR^(c)C(═NR^(i))NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),NR^(c)S(O)₂R^(b), C(═NOH)R^(b), C(═NO(C₁₋₆ alkyl))R^(b), andS(O)₂NR^(c)R^(d).

In some embodiments, Z is aryl, cycloalkyl, heteroaryl, orheterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6substituents selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹,CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a),OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), C(═NR^(i))NR^(c)R^(d),NR^(c)C(═NR^(i))NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is aryl, cycloalkyl, heteroaryl, orheterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6substituents selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂,OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),NR^(c)C(O)OR^(a), —C(═NR^(i))NR^(c)R^(d), NR^(c)C(═NR^(i))NR^(c)R^(d),S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), andS(O)₂NR^(c)R^(d).

In some embodiments, Z is aryl or heteroaryl, each optionallysubstituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo,C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, halosulfanyl,C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a),C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a),C(═NR^(i))NR^(c)R^(d), NR^(c)C(═NR^(i))NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), NRS(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is aryl or heteroaryl, each optionallysubstituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo,C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(a),NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a),C(═NR^(i))NR^(c)R^(d), NR^(c)C(═NR^(i))NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is phenyl or 5- or 6-membered heteroaryl, eachoptionally substituted with 1, 2, 3, 4, 5, or 6 substituents selectedfrom halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,halosulfanyl, C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂, OR^(a),SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),NR^(c)C(O)OR^(a), C(═NR^(i))NR^(c)R^(d), NR^(c)C(═NR^(i))NR^(c)R^(d),S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), andS(O)₂NR^(c)R^(d).

In some embodiments, Z is phenyl or 5- or 6-membered heteroaryl, eachoptionally substituted with 1, 2, 3, 4, 5, or 6 substituents selectedfrom halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a),C(═NR^(i))NR^(c)R^(d), NR^(c)C(═NR^(i))NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is phenyl optionally substituted with 1, 2, 3, 4,5, or 6 substituents selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄ hydroxyalkyl, C₁₋₄cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), —C(═NR^(i))NR^(c)R^(d),NR^(c)C(═NR^(i))NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is phenyl optionally substituted with 1, 2, 3, 4,5, or 6 substituents selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN,NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),NR^(c)C(O)OR^(c), C(═NR^(i))NR^(c)R^(d), NR^(c)C(═NR^(i))NR^(c)R^(d),S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), andS(O)₂NR^(c)R^(d).

In some embodiments, Z is cycloalkyl or heterocycloalkyl, eachoptionally substituted with 1, 2, 3, 4, 5, or 6 substituents selectedfrom halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,halosulfanyl, C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂, OR^(a),SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),NR^(c)C(O)OR^(a), C(═NR^(i))NR^(c)R^(d), NR^(c)C(═NR^(i))NR^(c)R^(d),S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), NRS(O)₂R^(b), andS(O)₂NR^(c)R^(d).

In some embodiments, Z is cycloalkyl or heterocycloalkyl, eachoptionally substituted with 1, 2, 3, 4, 5, or 6 substituents selectedfrom halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a),C(═NR^(i))NR^(c)R^(d), NR^(c)C(═NR^(i))NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, or cycloheptyl, each optionally substituted with 1, 2, 3, 4,5, or 6 substituents selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄ hydroxyalkyl, C₁₋₄cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), C(═NR^(i))NR^(c)R^(d),NR^(c)C(═NR^(i))NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is C₁₋₈ alkyl, C₂₋₈ alkenyl, or C₂₋₈ alkynyl,each optionally substituted with 1, 2, 3, 4, 5, or 6 substituentsselected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄haloalkyl, halosulfanyl, C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN,NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),NR^(c)C(O)OR^(a), C(═NR^(i))NR^(c)R^(d), NR^(c)C(═NR^(i))NR^(c)R^(d),S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), andS(O)₂NR^(c)R^(d). In some embodiments, Z is C₁₋₈ alkyl, C₂₋₈ alkenyl, orC₂₋₈ alkynyl, each optionally substituted with 1, 2, 3, 4, 5, or 6substituents selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂,OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),NR^(c)C(O)OR^(a), C(═NR^(i))NR^(c)R^(d), NR^(c)C(═NR^(i))NR^(c)R^(d),S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), andS(O)₂NR^(c)R^(d).

In some embodiments, Z is aryl, cycloalkyl, heteroaryl, orheterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6substituents independently selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄ hydroxyalkyl, C₁₋₄cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is aryl, cycloalkyl, heteroaryl, orheterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6substituents independently selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹,CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a),OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is aryl or heteroaryl, each optionallysubstituted with 1, 2, 3, 4, 5, or 6 substituents independently selectedfrom halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄haloalkyl,halosulfanyl, C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂, OR^(a),SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is aryl or heteroaryl, each optionallysubstituted with 1, 2, 3, 4, 5, or 6 substituents independently selectedfrom halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is phenyl or 5- or 6-membered heteroaryl, eachoptionally substituted with 1, 2, 3, 4, 5, or 6 substituentsindependently selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄ hydroxyalkyl, C₁₋₄cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is phenyl or 5- or 6-membered heteroaryl, eachoptionally substituted with 1, 2, 3, 4, 5, or 6 substituentsindependently selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN,NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is phenyl optionally substituted with 1, 2, 3, 4,5, or 6 substituents independently selected from halo, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄ hydroxyalkyl,C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is phenyl optionally substituted with 1, 2, 3, 4,5, or 6 substituents independently selected from halo, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₄cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is cycloalkyl or heterocycloalkyl, eachoptionally substituted with 1, 2, 3, 4, 5, or 6 substituentsindependently selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄ hydroxyalkyl, C₁₋₄cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is cycloalkyl or heterocycloalkyl, eachoptionally substituted with 1, 2, 3, 4, 5, or 6 substituentsindependently selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN,NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is C₁₋₈ alkyl, C₂₋₈ alkenyl, or C₂₋₈ alkynyl,each optionally substituted with 1, 2, 3, 4, 5, or 6 substituentsindependently selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄ hydroxyalkyl, C₁₋₄cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is C₁₋₈ alkyl, C₂₋₈ alkenyl, or C₂₋₈ alkynyl,each optionally substituted with 1, 2, 3, 4, 5, or 6 substituentsindependently selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, C₁₋₄, hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN,NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d) NR^(c)C(O)R^(b′)NR^(c)C(O)NR^(c)R^(d),NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl,cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substitutedwith 1, 2, 3, 4, 5, or 6 substituents independently selected from halo,C₁₋₄ alkyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄ hydroxyalkyl, C₁₋₄cyanoalkyl, Cy¹, CN, NO₂, OR^(a), C(O)NR^(c)R^(d), C(O)OR^(a),NR^(c)R^(d), NR^(c)C(O)R^(b), and S(O)₂R^(b).

In some embodiments, Z is C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl,cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substitutedwith 1, 2, 3, 4, 5, or 6 substituents independently selected from halo,C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN,NO₂, OR^(a), C(O)NR^(c)R^(d), C(O)OR^(a), NR^(c)R^(d), NR^(c)C(O)R^(b),and S(O)₂R^(b).

In some embodiments, Z is C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl,cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substitutedwith 1, 2, or 3 substituents independently selected from halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl,Cy¹, CN, NO₂, OR^(a), C(O)NR^(c)R^(d), C(O)OR^(a), NR^(c)R^(d),NR^(c)C(O)R^(b), and S(O)₂R^(b).

In some embodiments, Z is C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl,cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substitutedwith 1, 2, or 3 substituents independently selected from halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂,OR^(a), C(O)NR^(c)R^(d), C(O)OR^(a), NR^(c)R^(d), NR^(c)C(O)R^(b), andS(O)₂R^(b).

In some embodiments, Z is substituted with at least one substituentcomprising at least one CN group.

In some embodiments, Z is C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl,cycloalkyl, heteroaryl, or heterocycloalkyl, each substituted with atleast one CN or C₁₋₄ cyanoalkyl and optionally substituted with 1, 2, 3,4, or 5 further substituents selected from halo, C₁₋₄ alkyl, C₂₋₈alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄ hydroxyalkyl,C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, Z is C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl,cycloalkyl, heteroaryl, or heterocycloalkyl, each substituted with atleast one CN or C₁₋₄ cyanoalkyl and optionally substituted with 1, 2, 3,4, or 5 further substituents selected from halo, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₄cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, wherein the —(Y)_(n)—Z moiety is taken togetherwith i) A² to which said moiety is attached, ii) R⁵ or R⁶ of either T orV, and iii) the C or N atom to which said R⁵ or R⁶ of either T or V isattached to form a 4- to 20-membered aryl, cycloalkyl, heteroaryl, orheterocycloalkyl ring fused to the 5-membered ring formed by A¹, A², U,T, and V, wherein said 4- to 20-membered aryl, cycloalkyl, heteroaryl,or heterocycloalkyl ring is optionally substituted by 1, 2, 3, 4, or 5substituents independently selected from -(W)_(m)-Q.

In some embodiments, wherein the —(Y)_(n)—Z moiety is taken togetherwith i) A² to which said moiety is attached, ii) R⁵ or R⁶ of either T orV, and iii) the C or N atom to which said R⁵ or R⁶ of either T or V isattached to form a 4- to 8-membered aryl, cycloalkyl, heteroaryl, orheterocycloalkyl ring fused to the 5-membered ring formed by A¹, A², U,T, and V, wherein said 4- to 8-membered aryl, cycloalkyl, heteroaryl, orheterocycloalkyl ring is optionally substituted by 1, 2, 3, 4, or 5substituents independently selected from -(W)_(m)-Q.

In some embodiments, the —(Y)_(n)—Z moiety is taken together with i) A²to which said moiety is attached, ii) R⁵ or R⁶ of either T or V, andiii) the C or N atom to which said R⁵ or R⁶ of either T or V is attachedto form a 6-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkylring fused to the 5-membered ring formed by A¹, A², U, T, and V, whereinsaid 6-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ringis optionally substituted by 1, 2, or 3 substituents independentlyselected from halo, CN, NO₂, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,C₁₋₈ haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkylwherein said C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ haloalkyl,aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionallysubstituted by 1, 2 or 3 CN.

In some embodiments, Cy¹ and Cy² are independently selected from aryl,heteroaryl, cycloalkyl, and heterocycloalkyl, each optionallysubstituted by 1, 2, 3, 4 or 5 substituents independently selected fromhalo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄hydroxyalkyl, C₁₋₄ cyanoalkyl, CN, NO₂, OR^(a″), SR^(a″), C(O)R^(b″),C(O)NR^(c″)R^(d″), C(O)OR^(a″), OC(O)R^(b″), OC(O)NR^(c″)R^(d″),NR^(c″)R^(d″), NR^(c″)C(O)R^(b″), NR^(c″)C(O)OR^(a″), S(O)R^(b″),S(O)NR^(c″)R^(d″), S(O)₂R^(b″), and S(O)₂NR^(c″)R^(d″).

In some embodiments, Cy¹ and Cy² are independently selected from aryl,heteroaryl, cycloalkyl, and heterocycloalkyl, each optionallysubstituted by 1, 2, 3, 4 or 5 substituents independently selected fromhalo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, CN, NO₂,OR^(a″), SR^(a″), C(O)R^(b″), C(O)NR^(c″)R^(d″), C(O)OR^(a″),OC(O)R^(b″), OC(O)NR^(c″)R^(d″), NR^(c″)R^(d″), NR^(c″)C(O)R^(b″),NR^(c″)C(O)OR^(a″)S(O)R^(b″), S(O)NR^(c″)R^(d″), S(O)₂R^(b″), andS(O)₂NR^(c″)R^(d″).

In some embodiments, Cy¹ and Cy² are independently selected fromcycloalkyl and heterocycloalkyl, each optionally substituted by 1, 2, 3,4 or 5 substituents independently selected from halo, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, CN, NO₂, OR^(a″), SR^(a″),C(O)R^(b″), C(O)NR^(c″)R^(d″), C(O)OR^(a″),OC(O)R^(b″)OC(O)NR^(c″)R^(d″), NR^(C″)R^(d″), NR^(c″)C(O)R^(b″),NR^(c″)C(O)OR^(a″), S(O)R^(b″), S(O)NR^(c″)R^(d″), S(O)₂R^(b″), andS(O)₂NR^(c″)R^(d″).

In some embodiments, Cy¹ and Cy² are independently selected fromcycloalkyl optionally substituted by 1, 2, 3, 4 or 5 substituentsindependently selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, CN, NO₂, OR^(a″), SR^(a″), C(O)R^(b″),C(O)NR^(c″)R^(d″), C(O)OR^(a″), OC(O)R^(b″), OC(O)NR^(c″)R^(d″),NR^(c″)R^(d″), NR^(c″)C(O)R^(b″), NR^(c″)C(O)OR^(a″)S(O)R^(b″),S(O)NR^(c″)R^(d″), S(O)₂R^(b″), and S(O)₂NR^(c″)R^(d″).

In some embodiments, R¹, R², R³, and R⁴ are independently selected fromH, halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR⁷, SR⁷, C(O)R⁸,C(O)NR⁹R¹⁰, C(O)OR⁷OC(O)R⁸, OC(O)NR⁹R¹⁰, NR⁹R¹⁰, NR⁹C(O)R⁸,NR^(c)C(O)OR⁷, S(O)R⁸, S(O)NR⁹R¹⁰, S(O)₂R⁸, NR⁹S(O)₂R⁸, and S(O)₂NR⁹R¹⁰.

In some embodiments, R¹, R², R³, and R⁴ are independently selected fromH, halo, and C₁₋₄ alkyl.

In some embodiments, R¹, R², R³, and R⁴ are each H.

In some embodiments, R¹ is H, halo, or C₁₋₄ alkyl.

In some embodiments, R⁵ is H, halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, CN, NO₂, OR⁷, SR⁷, C(O)R⁸, C(O)NR⁹R¹⁰, C(O)OR⁷,OC(O)R⁸, OC(O)NR⁹R¹⁰, NR⁹R¹⁰, NR⁹C(O)R⁸, NR⁹C(O)OR⁷, S(O)R⁸, S(O)NR⁹R¹⁰,S(O)₂R⁸, NR⁹S(O)₂R⁸, or S(O)₂NR⁹R¹⁰.

In some embodiments, R⁵ is H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,halosulfanyl, CN, or NR⁹R¹⁰.

In some embodiments, R⁵ is H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN, orNR⁹R¹⁰.

In some embodiments, R⁵ is H.

In some embodiments, R⁶ is H or C₁₋₄ alkyl.

In some embodiments, R⁶ is H.

In some embodiments, R¹¹ and R¹² are independently selected from H,halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,halosulfanyl, C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂, OR^(a),SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),NR^(c)C(O)OR^(a), C(═NR^(i))NR^(c)R^(d), NR^(c)C(═NR^(i))NR^(c)R^(d),S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), C(═NOH)R^(b),C(═NO(C₁₋₆ alkyl)R^(b), and S(O)₂NR^(c)R^(d), wherein said C₁-g alkyl,C₂₋₈ alkenyl, or C₂₋₈ alkynyl, is optionally substituted with 1, 2, 3,4, 5, or 6 substituents independently selected from halo, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a),C(═NR^(i))NR^(c)R^(d), NR^(c)C(═NR^(i))NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), C(═NOH)R^(b), C(═NO(C₁₋₆alkyl))R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, R¹¹ and R¹² are independently selected from H,halo, OH, CN, (C₁₋₄)alkyl, (C₁₋₄)haloalkyl, halosulfanyl, SCN,(C₂₋₄)alkenyl, (C₂₋₄)alkynyl, (C₁₋₄)hydroxyalkyl, (C₁₋₄)cyanoalkyl,aryl, heteroaryl, cycloalkyl, and heterocycloalkyl.

In some embodiments, R¹¹ and R¹² are independently selected from H,halo, OH, CN, (C₁₋₄)alkyl, (C₁₋₄)haloalkyl, (C₂₋₄)alkenyl,(C₂₋₄)alkynyl, (C₁₋₄)hydroxyalkyl, (C₁₋₄)cyanoalkyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl.

In a preferred embodiment, the JAK-2 inhibitor is ruxolitinib (availablefrom Incyte Corp. and Novartis AG). In a preferred embodiment, the JAK-2inhibitor is ruxolitinib phosphate (available from Incyte Corp. andNovartis AG). In a preferred embodiment, the JAK-2 inhibitor is(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile.In a preferred embodiment, the JAK-2 inhibitor is the phosphate salt of(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile.In a preferred embodiment, the JAK-2 inhibitor is(3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile.In a preferred embodiment, the JAK-2 inhibitor is a compound of Formula(XXX):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. The preparation of this compound is described in U.S.Pat. Nos. 8,604,043, 7,834,022, 8,486,902, 8,530,485, 7,598,257,8,541,425, and 8,410,265 and U.S. Patent Application Publication Nos.2010/0298355 A1, 2008/0312258 A1, 2011/0082159 A1, 2011/0086810 A1,2013/0345157 A1, 2014/0018374 A1, 2014/0005210 A1, 2011/0223210 A1,2011/0224157 A1, 2007/0135461 A1, 2010/0022522 A1, 2013/0253193 A1,2013/0253191 A1, 2013/0253190 A1, 2010/0190981 A1, 2013/0338134 A1,2008/0312259 A1, 2014/0094477 A1, and 2014/0094476 A1, the disclosuresof which are incorporated by reference herein. In an embodiment, theJAK-2 inhibitor is a compound selected from the structures disclosed inU.S. Pat. Nos. 8,604,043, 7,834,022, 8,486,902, 8,530,485, 7,598,257,8,541,425, and 8,410,265 and U.S. Patent Application Publication Nos.2010/0298355 A1, 2008/0312258 A1, 2011/0082159 A1, 2011/0086810 A1,2013/0345157 A1, 2014/0018374 A1, 2014/0005210 A1, 2011/0223210 A1,2011/0224157 A1, 2007/0135461 A1, 2010/0022522 A1, 2013/0253193 A1,2013/0253191 A1, 2013/0253190 A1, 2010/0190981 A1, 2013/0338134 A1,2008/0312259 A1, 2014/0094477 A1, and 2014/0094476 A1, the disclosuresof which are incorporated by reference herein.

Ruxolitinib may be prepared according to the procedures given in thereferences above, or by the procedure of Example 67 of U.S. Pat. No.7,598,257, the disclosure of which is specifically incorporated byreference herein. Briefly, the preparation is as follows:

Step 1. (2E)- and (2Z)-3-Cyclopentylacrylonitrile. To a solution of 1.0M potassium tert-butoxide in THF (235 mL) at 0° C. was added dropwise asolution of diethyl cyanomethylphosphonate (39.9 mL, 0.246 mol) in TBF(300 mL). The cold bath was removed and the reaction was warmed to roomtemperature followed by recooling to 0° C., at which time a solution ofcyclopentanecarbaldehyde (22.0 g, 0.224 mol) in THF (60 mL) was addeddropwise. The bath was removed and the reaction warmed to ambienttemperature and stirred for 64 hours. The mixture was partitionedbetween diethyl ether and water, the aqueous was extracted with threeportions of ether, followed by two portions of ethyl acetate. Thecombined extracts were washed with brine, then dried over sodiumsulfate, filtered and concentrated in vacuo to afford a mixturecontaining 24.4 g of olefin isomers which was used without furtherpurification (89%). ¹H NMR (400 MHz, CDCl3): δ 6.69 (dd, 1H, transolefin), 6.37 (t, 1H, cis olefin), 5.29 (dd, 1H, trans olefin), 5.20 (d,1H, cis olefin), 3.07-2.95 (m, 1H, cis product), 2.64-2.52 (m, 1H, transproduct), 1.98-1.26 (m, 16H).

Step 2. (3R)- and(3S)-3-Cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile.To a solution of4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine(15.0 g, 0.0476 mol) in ACN (300 mL) was added3-cyclopentylacrylonitrile (15 g, 0.12 mol) (as a mixture of cis andtrans isomers), followed by DBU (15 mL, 0.10 mol). The resulting mixturewas stirred at room temperature overnight. The ACN was evaporated. Themixture was diluted with ethyl acetate, and the solution was washed with1.0 N HCl. The aqueous layer was back-extracted with three portions ofethyl acetate. The combined organic extracts were washed with brine,dried over sodium sulfate, filtered and concentrated. The crude productwas purified by silica gel chromatography (gradient of ethylacetate/hexanes) to yield a viscous clear syrup, which was dissolved inethanol and evaporated several times to remove ethyl acetate, to afford19.4 g of racemic adduct (93%). The enantiomers were separated bypreparative-HPLC, (OD-H column, 15% ethanol/hexanes) and used separatelyin the next step to generate their corresponding final product. Thefinal products (see Step 3) stemming from each of the separatedenantiomers were found to be active JAK inhibitors; however, the finalproduct stemming from the second peak to elute from the preparative-HPLCwas more active than its enantiomer. The products may be isolated bypreparative HPLC or other means known to those of skill in the art foruse in Step 3 below. ¹H NMR (300 MHz, CDCl3): δ 8.85 (s, 1H), 8.32 (s,2H), 7.39 (d, 1H), 6.80 (d, 1H), 5.68 (s, 2H), 4.26 (dt, 1H), 3.54 (t,2H), 3.14 (dd, 1H), 2.95 (dd, 1H), 2.67-2.50 (m, 1H), 2.03-1.88 (m, 1H),1.80-1.15 (m, 7H), 0.92 (t, 2H), −0.06 (s, 9H); MS(ES): 437 (M+1).

Step 3. To a solution of3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile(6.5 g, 0.015 mol, R or S enantiomer as isolated above) in DCM (40 mL)was added TFA (16 mL) and this was stirred for 6 hours. The solvent andTFA were removed in vacuo. The residue was dissolved in DCM andconcentrated using a rotary evaporator two further times to remove asmuch as possible of the TFA. Following this, the residue was stirredwith ethylenediamine (4 mL, 0.06 mol) in methanol (30 mL) overnight. Thesolvent was removed in vacuo, water was added and the product wasextracted into three portions of ethyl acetate. The combined extractswere washed with brine, dried over sodium sulfate, decanted andconcentrated to afford the crude product which was purified by flashcolumn chromatography (eluting with a gradient of methanol/DCM). Theresulting mixture was further purified by preparative-HPLC/MS (C18eluting with a gradient of ACN/H2O containing 0.15% NH4OH) to affordproduct (2.68 g, 58%). ¹H NMR (400 MHz, D6-dmso): δ 12.11 (br s, 1H),8.80 (s, 1H), 8.67 (s, 1H), 8.37 (s, 1H), 7.60 (d, 1H), 6.98 (d, 1H),4.53 (dt, 1H), 3.27 (dd, 1H), 3.19 (dd, 1H), 2.48-2.36 (m, 1H),1.86-1.76 (m, 1H), 1.68-1.13 (m, 7H); MS(ES): 307 (M+1).

Ruxolitinib prepared according to the steps above, or any otherprocedure, may be used as its free base for the compositions and methodsdescribed heren. Ruxolitinib may also be used in a salt form. Forexample, a crystalline phosphoric acid salt of(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrilemay be prepared from the free base as follows according to the proceduregiven in Example 2 of U.S. Pat. No. 8,722,693, the disclosure of whichis specifically incorporated herein by reference. To a test tube wasadded(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile(153.5 mg) and phosphoric acid (56.6 mg) followed by isopropyl alcohol(IPA) (5.75 mL). The resulting mixture was heated to clear, cooled toroom temperature, and then stirred for another 2 hours. The precipitatewas collected by filtration and the cake was washed with 0.6 mL of coldIPA. The cake was dried under vacuum to constant weight to provide thefinal salt product (171.7 mg). The phosphroic acid salt is a 1:1 salt by¹H NMR and crystallinity is confirmed by X-ray powder diffraction(XRPD). Differential scanning calorimetry (DSC) of the produce yields asharp melting peak at about 198.7° C.

In an embodiment, the JAK-2 inhibitor is a compound of Formula (XXXI):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, wherein:L is SO₂ or CO;R¹ is C₁₋₆ alkyl, C₃₋₇ cycloalkyl, phenyl, 5- or 6-membered heteroaryl,indolyl, NR²R³, or OR⁴, wherein said alkyl, cycloalkyl, phenyl, orheteroaryl is optionally substituted with 1, 2, or 3 substituentsindependently selected from F, CN, and C₁₋₄ alkyl;R² and R³ are independently selected from H, C₁₋₄ alkyl, and phenyl; andR⁴ is C₁₋₆ alkyl, phenyl, or benzyl.

In some embodiments, when L is SO₂, then R¹ is other than OR⁴.

In some embodiments, when L is SO₂, then R¹ is C₁₋₆ alkyl, C₃₋₇cycloalkyl, phenyl, 5- or 6-membered heteroaryl, or NR²R³, wherein saidalkyl, cycloalkyl, phenyl, or heteroaryl is optionally substituted with1, 2, or 3 substituents independently selected from F and C₁₋₄ alkyl.

In some embodiments, when L is CO, then R¹ is C₃₋₇ cycloalkyl, phenyl,5- or 6-membered heteroaryl, indolyl, NR²R³, or OR⁴, wherein saidcycloalkyl, phenyl, or heteroaryl is optionally substituted with 1, 2,or 3 substituents independently selected from CN and C₁₋₄ alkyl.

In some embodiments, L is SO₂.

In some embodiments, L is CO.

In some embodiments, R¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl,t-butyl, 2-methylprop-1-yl, 1-methylprop-1-yl, each optionallysubstituted with 1, 2, or 3 F.

In some embodiments, R¹ is C₁₋₄ alkyl.

In some embodiments, R¹ is ethyl.

In some embodiments, R¹ is C₃₋₇ cycloalkyl optionally substituted byC₁₋₄ alkyl.

In some embodiments, R¹ is phenyl optionally substituted with F, methyl,or CN.

In some embodiments, R¹ is 5-membered heteroaryl selected from thienyl,pyrazolyl, pyrrolyl, 1,2,4-oxadiazolyl, and isoxazolyl, each optionallysubstituted with C₁₋₄ alkyl.

In some embodiments, R¹ is pyridinyl.

In some embodiments, R¹ is NR²R³ or OR⁴.

In some embodiments, L is SO₂ and R¹ is C₁₋₆ alkyl.

In an embodiment, the JAK-2 inhibitor is baricitinib (available fromIncyte Corp. and Eli Lilly & Co.). In an embodiment, the JAK-2 inhibitoris2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile.In an embodiment, the JAK-2 inhibitor is a compound of Formula (XXXII):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. The preparation of this compound is described in U.S.Pat. Nos. 8,158,616 and 8,420,629, U.S. Patent Application PublicationNos. 2009/0233903 A1; 2013/0225556 A1; and, 2012/0077798 A1, andInternational Patent Application Publication No. WO 2014/0028756, thedisclosures of which are incorporated by reference herein. In anembodiment, the JAK-2 inhibitor is a compound described in U.S. Pat.Nos. 8,158,616 and 8,420,629, U.S. Patent Application Publication Nos.2009/0233903 A1; 2013/0225556 A1; and, 2012/0077798 A1, andInternational Patent Application Publication No. WO 2014/0028756, thedisclosures of which are incorporated by reference herein.

In an embodiment, the JAK-2 inhibitor is a compound of Formula (XXXIII):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, wherein:

-   Q and Z are independently selected from N and CR¹; n is 1, 2 or 3;-   R¹ is independently selected from hydrogen, halogen, R², OR², OH,    R⁴, OR⁴, CN, CF₃, (CH₂)_(n)N(R²)₂, NO₂, R²R⁴, SO₂R⁴, NR²SO₂R³, COR⁴,    NR²COR³, CO₂H, CO₂R², NR²COR⁴, R²CN, R²CN, R²OH, R²OR³ and OR⁵R⁴; or    two R¹ substituents together with the carbons which they are    attached to form an unsaturated 5 or 6 membered heterocyclyl;-   R² is substituted or unsubstituted C₁₋₄alkyl or substituted or    unsubstituted C₁₋₄ alkylene where up to 2 carbon atoms can be    optionally replaced with CO, NR^(Y), CONR^(Y), S, SO₂ or O;-   R³ is R², C₂₋₄ alkenyl or substituted or unsubstituted aryl;-   R⁴ is NH₂, NHR², N(R′)₂, substituted or unsubstituted morpholino,    substituted or unsubstituted thiomorpholino, substituted or    unsubstituted thiomorpholino-1-oxide, substituted or unsubstituted    thiomorpholino-1, 1-dioxide, substituted or unsubstituted    piperazinyl, substituted or unsubstituted piperidinyl, substituted    or unsubstituted pyridinyl, substituted or unsubstituted    pyrrolidinyl, substituted or unsubstituted pyrrolyl, substituted or    unsubstituted oxazolyl, substituted or unsubstituted imidazolyl,    substituted or unsubstituted tetrahydrofuranyl and substituted or    unsubstituted tetrahydropyranyl;-   R⁵ is substituted or unsubstituted C₁₋₄alkylene;-   R⁶-R¹⁰ are independently selected from H, R^(X)CN, halogen,    substituted or unsubstituted C_(M)alkyl, OR¹, CO₂R¹, N(R′)₂, NO₂,    CON(R′)_(2J) SO₂N(R^(Y))₂, N(SO₂R^₂, substituted or unsubstituted    piperazinyl, N(R^(Y))SO₂R² and CF₃; R^(x) is absent or substituted    or unsubstituted Ci₋₆alkylene wherein up to 2 carbon atoms can be    optionally replaced with CO, NSO₂R¹, NR^(Y), CONR^(Y), S, SO₂ or O;    R^(γ) is H or substituted or unsubstituted C₁₋₄ alkyl; and-   R¹¹ is selected from H, halogen, substituted or unsubstituted C₁₋₄    alkyl, OR², CO₂R², CN, CON(R′)₂ and CF₃, or an enantiomer thereof.

In a preferred embodiment, the JAK-2 inhibitor is momelotinib (GileadSciences). Momelotinib is also known as CYT-387. In a preferredembodiment, the JAK-2 inhibitor isN-(cyanomethyl)-4-(2-((4-morpholinophenyl)amino)pyrimidin-4-yl)benzamide.In a preferred embodiment, the JAK-2 inhibitor is a compound of Formula(XXXIV):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. The preparation of this compound is described in U.S.Pat. No. 8,486,941 and U.S. Patent Application Publication Nos.2010/0197671 A1; 2014/0005180 A1; 2014/0011803 A1; and, 2014/0073643 A1,the disclosures of which are incorporated by reference herein. In anembodiment, the JAK-2 inhibitor is a compound described in U.S. Pat. No.8,486,941 and U.S. Patent Application Publication Nos. 2010/0197671 A1;2014/0005180 A1; 2014/0011803 A1; and, 2014/0073643 A1, the disclosuresof which are incorporated by reference herein.

In an embodiment, the JAK-2 inhibitor is a compound of Formula (XXXV):

or a tautomer thereof, or a clathrate thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof,wherein:

-   X₄₁ is O, S, or NR₄₂-   X₄₂ is CR₄₄ or N;-   Y₄₀ is N or CR₄₃;-   Y₄₁ is N or CR₄₅;-   Y₄₂, for each occurrence, is independently N, C or CR₄₆;-   Z is OH SH, or NHR₇;-   R₄₁ is —H, —OH, —SH, an optionally substituted alkyl, an optionally    substituted alkenyl, an optionally substituted alkynyl, an    optionally substituted cycloalkyl, an optionally substituted    cycloalkenyl, an optionally substituted heterocyclyl, an optionally    substituted aryl, an optionally substituted heteroaryl, an    optionally substituted aralkyl, an optionally substituted    heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a    heteroalkyl, an alkoxy or cycloalkoxy, a haloalkoxy, —NR₁₀R₁₁, —OR₇,    —C(O)R₇, —C(O)OR₇, —C(S)R₇, —C(O)SR₇, —C(S)SR₇, —C(S)OR₇,    —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇,    —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(₈)OR₇, —SC(O)R₇, —SC(O)OR₇,    —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇, —OC(O)NR₁₀R₁₁,    —OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁,    —SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,    —NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇, —NR₇C(NR₈)OR₇,    —NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —SR₇,    —S(O)_(p)R₇, —OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁,    —S(O)_(p)OR₇, —NR₈S(O)_(P)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇,    —S(O)_(p)NR₁₀R₁₁, —SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁,    —OP(O)(OR₇)₂, or —SP(O)(OR₇)₂;-   R₄₂ is —H, an optionally substituted alkyl, an optionally    substituted alkenyl, an optionally substituted alkynyl, an    optionally substituted cycloalkyl, an optionally substituted    cycloalkenyl, an optionally substituted heterocyclyl, an optionally    substituted aryl, an optionally substituted heteroaryl, an    optionally substituted aralkyl, an optionally substituted    heteraralkyl, hydroxyalkyl, alkoxyalkyl, a haloalkyl, a heteroalkyl,    —C(O)R₇, —(CH₂)_(m)C(O)OR₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁,    —S(O)_(p)R₇, —S(O)_(p)OR₇, or —S(O)_(p)NR₁₀R₁₁;-   R₄₃ and R₄₄ are, independently, —H, —OH, an optionally substituted    alkyl, an optionally substituted alkenyl, an optionally substituted    alkynyl, an optionally substituted cycloalkyl, an optionally    substituted cycloalkenyl, an optionally substituted heterocyclyl, an    optionally substituted aryl, an optionally substituted heteroaryl,    an optionally substituted aralkyl, an optionally substituted    heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro,    guanadino, a haloalkyl, a heteroalkyl, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,    —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,    —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, —S(O)_(p)NR₁₀R₁₁, or R₄₃ and R₄₄ taken    together with the carbon atoms to which they are attached form an    optionally substituted cycloalkenyl, an optionally substituted aryl,    an optionally substituted heterocyclyl, or an optionally substituted    heteroaryl;-   R₄₅ is —H, —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆, —O(CH₂)_(m)OH,    —O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH,    —S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁,    —OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇,    —OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCR₂C(O)OR₇,    —NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁,    —NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇, —SS(O)_(p)R₇, —NR₇S(O)_(p)R₇,    —OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁,    —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,    —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁,    —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —NR₇C(N₈)R₇,    —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,    —SC(NR₈)NR₁₀R₁₁, or —NR₇C(N₈)NR₁₀R₁₁;-   R₄₆, for each occurrence, is independently, selected from the group    consisting of H, an optionally substituted alkyl, an optionally    substituted alkenyl, an optionally substituted alkynyl, an    optionally substituted cycloalkyl, an optionally substituted    cycloalkenyl, an optionally substituted heterocyclyl, an optionally    substituted aryl, an optionally substituted heteroaryl, an    optionally substituted aralkyl, an optionally substituted    heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a    heteroalkyl, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,    —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,    —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁;-   R₇ and R₈, for each occurrence, are, independently, —H, an    optionally substituted alkyl, an optionally substituted alkenyl, an    optionally substituted alkynyl, an optionally substituted    cycloalkyl, an optionally substituted cycloalkenyl, an optionally    substituted heterocyclyl, an optionally substituted aryl, an    optionally substituted heteroaryl, an optionally substituted    aralkyl, or an optionally substituted heteraralkyl;-   R₁₀ and R₁₁, for each occurrence, are independently —H, an    optionally substituted alkyl, an optionally substituted alkenyl, an    optionally substituted alkynyl, an optionally substituted    cycloalkyl, an optionally substituted cycloalkenyl, an optionally    substituted heterocyclyl, an optionally substituted aryl, an    optionally substituted heteroaryl, an optionally substituted    aralkyl, or an optionally substituted heteraralkyl; or R₁₀ and R₁₁,    taken together with the nitrogen to which they are attached, form an    optionally substituted heterocyclyl or an optionally substituted    heteroaryl;-   R₂₆, for each occurrence is, is independently, a lower alkyl;-   p, for each occurrence, is, independently, 1 or 2; and-   m, for each occurrence, is independently, 1, 2, 3, or 4.

In an embodiment, the JAK-2 inhibitor is a compound of Formula (XXXVI):

or a tautomer thereof, or a clathrate thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof,wherein:

-   X₄₅ is CR₅₄ or N;-   Z1 is —OH or —SH;-   R₅₆ is selected from the group consisting of —H, methyl, ethyl,    isopropyl, and cyclopropyl;-   R₅₂ is selected from the group consisting of —H, methyl, ethyl,    n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, —(CH₂)₂OCH₃,    —CH₂C(O)OH, and —C(O)N(CH₃)₂;-   R₅₃ and R₅₄ are each, independently, —H, methyl, ethyl, or    isopropyl; or R₅₃ and R₅₄ taken together with the carbon atoms to    which they are attached form a phenyl, cyclohexenyl, or cyclooctenyl    ring; and-   R₅₅ is selected from the group consisting of —H, —OH, —OCH₃, and    —OCH₂CH₃.

In a preferred embodiment, the JAK-2 inhibitor is ganetespib. In apreferred embodiment, the JAK-2 inhibitor is5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one.In a preferred embodiment, the JAK-2 inhibitor is a compound of Formula(XXXVII):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. The preparation of this compound is described in U.S.Pat. Nos. 7,825,148 and 8,628,752, U.S. Patent Application PublicationNos. 2006/0167070 A1; 2014/0024030 A1; 2014/0051665 A1; 2014/0045908 A1;2012/0128665 A1; 2013/0109045 A1, and 2014/0079636 A1, and,International Patent Application Publication No. WO 2013/170182; WO2013/028505; WO 2013/067162; WO 2013/173436; WO 2013/006864; WO2012/162584; WO 2013/170159; WO 2013/067165; WO 2013/074594; WO2012/162372; WO 2012/162293; and WO 2012/155063, the disclosures ofwhich are incorporated by reference herein. In an embodiment, the JAK-2inhibitor is a compound described in U.S. Pat. Nos. 7,825,148 and8,628,752, U.S. Patent Application Publication Nos. 2006/0167070 A1;2014/0024030 A1; 2014/0051665 A1; 2014/0045908 A1; 2012/0128665 A1;2013/0109045 A1, and 2014/0079636 A1, and, International PatentApplication Publication No. WO 2013/170182; WO 2013/028505; WO2013/067162; WO 2013/173436; WO 2013/006864; WO 2012/162584; WO2013/170159; WO 2013/067165; WO 2013/074594; WO 2012/162372; WO2012/162293; and WO 2012/155063, the disclosures of which areincorporated by reference herein.

In an embodiment, the JAK-2 inhibitor is a compound of Formula(XXXVIII):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, wherein the compound is defined by the following (I) or(II).(I): X represents CH or N; R₁ represents a halogen;R₂ represents: (1) H, (2) a halogen, (3) cyano, (4) a group representedby the following general formula [2]:

(wherein * indicates the binding position; and R^(C), R^(D) and R^(E)are the same or different and each represents (a) H, or (b) alkyloptionally substituted by hydroxy or alkoxy, or alternatively two ofR^(C), R^(D) and R^(E) are taken together with the adjacent C torepresent a N-containing saturated heterocyclic group and the other oneis H, the saturated heterocyclic group optionally substituted byalkylsulfonyl),(5) a group represented by the following general formula [3]:

(wherein * has the same meaning as described above; and R^(F) and R^(G)are the same or different and each represents (a) H, (b) alkyloptionally substituted by one or two groups selected from the groupconsisting of hydroxy, amino, dialkylamino, a saturated cyclic aminogroup, alkylcarbonylamino, alkylsulfonylamino, aryl, heteroaryloptionally substituted by alkyl, tetrahydrofuranyl, and carbamoyl, (c)alkylcarbonyl, (d) alkylsulfonyl, (e) carbamoyl, or (f) heteroaryloptionally substituted by alkyl, or alternatively R^(F) and R^(G) aretaken together with the adjacent N to represent a saturated cyclic aminogroup, which may optionally be substituted by one or two groups selectedfrom the group consisting of (a) halogen, (b) cyano, (c) hydroxy, (d)alkyl optionally substituted by one or two groups selected from thegroup consisting of hydroxy, alkoxy, amino, alkoxycarbonylamino,alkylsulfonylamino, and alkylcarbonylamino, (e) cycloalkyl, (f)haloalkyl, (g) alkoxy, (h) oxo, (i) a group represented by the followinggeneral formula [4]:

(wherein * has the same meaning as described above; and R^(H) representsalkyl or aryl), (j) a group represented by the following general formula[5]:

(wherein * has the same meaning as described above; and R^(I) and R^(J)are the same or different and each represents H, alkyl, carbamoyl,alkylcarbonyl, or alkylsulfonyl), (k) a group represented by thefollowing general formula [6]:

(wherein * has the same meaning as described above; and R^(K) representsalkyl, hydroxy, amino, alkylamino, dialkylamino, cycloalkylamino,(cycloalkyl)alkylamino, (hydroxyalkyl)amino, (alkoxyalkyl)amino, alkoxy,alkylsulfonylamino, or a saturated cyclic amino group), and (1) asaturated cyclic amino group optionally substituted by hydroxy; and thesaturated cyclic amino group, which is formed by combining R^(F), R^(G)and the adjacent N, may form a spiro-linkage with a group represented bythe following general formula [7A] or [7B]:

(wherein has the same meaning as described above)),(6) a group represented by the following general formula [8]:

(wherein * has the same meaning as described above; and R^(L) represents(a) alkyl, (b) hydroxy, (c) alkoxy, (d) saturated cyclic amino groupoptionally substituted by alkyl or alkylsulfonyl, or (e) an aminooptionally substituted by one or two groups selected from the groupconsisting of alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl; haloalkyl,dialkylaminoalkyl, alkoxyalkyl, and hydroxyalkyl),(7) a group represented by the following general formula [9]:

(wherein * has the same meaning as described above; and R^(M), R^(N) andR^(O) are the same or different and each represents H, halogen, cyano,alkoxy, carbamoyl, sulfamoyl, monoalkylaminosulfonyl, or alkylsulfonyl,or alternatively two of R^(M), R^(N) and R^(O) are taken together torepresent methylenedioxy),(8) —OR^(P) (R^(P) represents an alkyl optionally substituted by a groupselected from the group consisting of hydroxy, dialkylamino, alkoxy,tetrahydrofuranyl, and cycloalkyl, or an optionally O-containingsaturated cyclic group optionally substituted by hydroxy), or(9) a heteroaryl optionally substituted by one or two groups selectedfrom the group consisting of cyano, halogen, hydroxy, alkoxy,alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl,hydroxycarbonyl and alkoxyalkyl;R₃ represents H or hydroxy;R₂ represents H or alkyl; andR₅ represents H or alkyl;(II): X represents —CR^(A);R^(A) represents a group represented by the following general formula[10]:

(wherein * has the same meaning as described above; and R^(B) represents(a) amino optionally substituted by one or two groups selected from thegroup consisting of alkyl, cycloalkyl, (cycloalkyl)alkyl, andalkoxyalkyl, (b) alkoxy, (c) hydroxy, or (d) a saturated cyclic aminogroup);R₁ represents a halogen;R₂ represents H;R₃ represents E or hydroxy;R₄ represents H or alkyl; andR₅ represents H or alkyl.

In a preferred embodiment, the JAK-2 inhibitor is NS-018. In anembodiment, the JAK-2 inhibitor is(S)—N²-(1-(4-fluorophenyl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-N⁴-(pyrazin-2-yl)pyrimidine-2,4-diamine.NS-018 has been described in Nakaya, et al., Blood Cancer J. 2014, 4,e174. In an embodiment, the JAK-2 inhibitor has the chemical structureshown in Formula (XXXIX):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. The preparation of this compound is described in U.S.Pat. Nos. 8,673,891 and 8,586,591, U.S. Patent Application PublicationNos. 2011/0288065 A1 and 2013/0131082 A1, and International PatentApplication Publication No. WO 2012/020787 and WO 2012/020786, thedisclosures of which are incorporated by reference herein. In anembodiment, the JAK-2 inhibitor is a compound described in U.S. Pat.Nos. 8,673,891 and 8,586,591, U.S. Patent Application Publication Nos.2011/0288065 A1 and 2013/0131082 A1, and International PatentApplication Publication No. WO 2012/020787 and WO 2012/020786, thedisclosures of which are incorporated by reference herein.

In an embodiment, the JAK-2 inhibitor is a compound of Formula (XL):

or a stereoisomer, tautomer, or pharmaceutically acceptable salt,solvate, hydrate, cocrystal, or prodrug thereof, wherein:

-   Y is C₁₋₄ alkyl;-   X is C₁₋₄ alkyl;-   R is

any of which are optionally fused with a 5 or 6 membered carbocycle orheterocycle having one heteroatom selected from NR³ or S, said fusedcarbocycle or heterocycle being optionally substituted with 0-3 R¹.

-   R¹ is H, halo, CN, C₁₋₆ alkyl substituted with 0-3 R^(c), CF₃,    CONR^(a)R^(a), NR^(a)R^(a), COOR^(b), SO₂—(C₁₋₄)alkyl, C(O)R^(d),    cycloalkyl substituted with 0-3 R^(e), furanyl, tetrahydropyranyl,    or pyridinyl;-   R² is absent, H, C₁₋₆ alkyl substituted with 0-3 R^(c),    C(O)O—(C₁₋₄)alkyl, SO₂—(C₁₋₄)alkyl, cycloalkyl substituted with 0-3    R^(e), or tetrahydropyranyl;-   R³ is absent, H, or C(O)O—(C₁₋₄)alkyl;-   R^(a) is H, C₁₋₆ alkyl substituted with 0-3 R^(e), C₃₋₆ cycloalkyl    substituted with 0-3 R^(e), tetrahydropyranyl, or    dioxotetrahydrothiophenyl;-   R^(b) is H or C₁₋₆ alkyl;-   R^(c) is H, halo, CN, OH, O—(C₁₋₄)alkyl,    O—(C₁₋₄)alkyl-O—(C₁₋₄)alkyl, NH₂, N(C₁₋₄ alkyl)₂, C(O)N(C₁₋₄    alkyl)₂, SO₂—(C₁₋₄)alkyl, or morpholinyl or piperazinyl, either of    which are optionally substituted with 0-1 C₁₋₄ alkyl;-   R^(d) is C₁₋₆ alkyl, or azeridinyl, azetidinyl, pyrrolidinyl,    piperidinyl, morpholinyl, piperazinyl, dioxidothiomorpholinyl or    tetrahydropyranyl, any of which are substituted with 0-2 R^(e); and-   R^(e) is H, halo, CN, C₁₋₄ alkyl, OH, O—(C₁₋₄)alkyl,    SO₂—(C₁₋₄)alkyl, NHC(O)—(C₁₋₄)alkyl, morpholinyl, OC(O)—(C₁₋₄)alkyl,    C(O)N(C₁₋₄ alkyl)₂, or O—(C₁₋₄)alkyl-O—(C₁₋₄)alkyl.

In an embodiment, the JAK-2 inhibitor is a compound of Formula (XL),wherein:

-   R is:

any of which are optionally substituted with 0-3 R¹.

In an embodiment, the JAK-2 inhibitor is a compound of Formula (XL),wherein Y is methyl and X is ethyl.

In another embodiment, the JAK-2 inhibitor is a compound of Formula(XL), wherein:

-   R is:

In an embodiment, the JAK-2 inhibitor is a compound of Formula (XL),wherein:

-   R is:

any of which are optionally substitute with 0-2 R¹.

In an embodiment, the JAK-2 inhibitor is a compound of Formula (XL),wherein

-   R is:

-   R¹ is H, halo, CN, C₁₋₆ alkyl substituted with 0-3 R^(c), CF₃,    CONR^(a)R^(a), COOR^(b), SO₂—(C₁₋₄)alkyl, C(O)R^(d), cycloalkyl    substituted with 0-3 R^(e), or pyridinyl;-   R^(a) is H, C₁₋₆ alkyl substituted with 0-3 R^(e), C₃₋₆ cycloalkyl    substituted with 0-3 R^(e), tetrahydropyranyl or    dioxotetrahydrothiophenyl;-   R^(b) is H or C₁₋₆ alkyl;-   R^(c) is H, halo, OH, O—(C₁₋₄)alkyl, SO₂—(C₁₋₄)alkyl or morpholinyl;-   R^(d) is C₁₋₆ alkyl, or azetidinyl, pyrrolidinyl, morpholinyl,    piperazinyl or dioxidothiomorpholinyl, any of which are substituted    with 0-2 R^(e);-   R^(e) is H, halo, CN, OH, O—(C₁₋₄)alkyl, SO₂—(C₁₋₄)alkyl,    NHC(O)—(C₁₋₄)alkyl or morpholinyl.

In an embodiment, the JAK-2 inhibitor is a compound of Formula (XL),wherein:

-   R is:

-   R¹ is H, halo, C₁₋₆ alkyl substituted with 0-3 R^(c), CF₃,    CONR^(a)R^(a), COOR^(b), C(O)R^(d), cycloalkyl substituted with 0-3    R^(e) or furanyl;-   R² is H, C₁₋₆ alkyl substituted with 0-3 R^(c), SO₂—(C₁₋₄)alkyl,    cycloalkyl substituted with 0-3 R^(e), or tetrahydropyranyl;-   R^(a) is H, or C₁₋₆ alkyl substituted with 0-3 R^(e);-   R^(b) is H or C₁₋₆ alkyl;-   R^(c) is H, halo, CN, OH, O—(C₁₋₄)alkyl,    O—(C₁₋₄)alkyl-O—(C₁₋₄)alkyl, NH₂, N(C₁₋₄ alkyl)₂, C(O)N(C₁₋₄    alkyl)₂, SO₂—(C₁₋₄)alkyl, or morpholinyl or piperazinyl, either of    which are optionally substituted with 0-1 C₁₋₄ alkyl;-   R^(d) is C₁₋₆ alkyl, or morpholinyl, piperazinyl or    dioxidothiomorpholinyl, any of which are substituted with 0-2 R^(e);    and-   R^(e) is H, C₁₋₄ alkyl, CN, OH, NHC(O)—(C₁₋₄)alkyl or morpholinyl.

In an embodiment, the JAK-2 inhibitor is a compound of Formula (XL),wherein:

-   R is:

-   R¹ is C₁₋₆ alkyl substituted with 0-3 R^(c); and-   R² is C₁₋₆ alkyl.

In a preferred embodiment, the JAK-2 inhibitor is BMS-911543. In apreferred embodiment, the JAK-2 inhibitor isN,N-dicyclopropyl-4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide.In a preferred embodiment, the JAK-2 inhibitor is a compound of Formula(XLI):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. The preparation of this compound is described in U.S.Pat. Nos. 8,673,933 and 8,202,881 and U.S. Patent ApplicationPublication Nos. 2013/0225551 A1 and 2011/0059943 A1, the disclosures ofwhich are incorporated by reference herein. In an embodiment, the JAK-2inhibitor is a compound described in U.S. Pat. Nos. 8,673,933 and8,202,881 and U.S. Patent Application Publication Nos. 2013/0225551 A1and 2011/0059943 A1, the disclosures of which are incorporated byreference herein.

In a preferred embodiment, the JAK-2 inhibitor is gandotinib. In apreferred embodiment, the JAK-2 inhibitor is3-(4-chloro-2-fluorobenzyl)-2-methyl-N-(5-methyl-1H-pyrazol-3-yl)-8-(morpholinomethyl)imidazo[1,2-b]pyridazin-6-amine.In a preferred embodiment, the JAK-2 inhibitor is a compound of Formula(XLII):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. The preparation of this compound is described in U.S.Pat. No. 7,897,600 and U.S. Patent Application Publication Nos.2010/0152181 A1 and 2010/0286139 A1, the disclosures of which areincorporated by reference herein. In an embodiment, the JAK-2 inhibitoris a compound described in U.S. Pat. No. 7,897,600 and U.S. PatentApplication Publication Nos. 2010/0152181 A1 and 2010/0286139 A1, thedisclosures of which are incorporated by reference herein.

In an embodiment, the JAK-2 inhibitor is a compound of Formula (XLIII):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, wherein:

-   R^(x) and R^(y) are independently selected from the group consisting    of -T-R³ and -L-Z—R³;-   Q′ is selected from the group consisting of —CR^(6″)═CR^(6″)— and    wherein said —CR^(6″)═CR^(6″)— may be a cis or trans double bond or    a mixture thereof,-   R¹ is -T-(Ring D);-   Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic    ring selected from the group consisting of aryl, heteroaryl,    heterocyclyl, and carbocyclyl, said heteroaryl or heterocyclyl ring    having 1-4 ring heteroatoms selected from the group consisting of    nitrogen, oxygen, and sulfur, wherein each substitutable ring carbon    of Ring D is independently substituted by oxo, -T-R⁵ or -V-Z—R⁵, and    each substitutable ring nitrogen of Ring D is independently    substituted by —R⁴;-   T is a valence bond or —(C(R^(6′))₂)-A-;-   A is a valence bond or a C₁-C₃ alkylidene chain wherein a methylene    unit of said C₁₋₃ alkylidene chain is optionally replaced by —O—,    —S—, —N(R⁴)—, —CO—, —CONH—, —NHCO—, —SO₂—, —SO₂NH—, —NHSO₂—, —CO₂—,    —OC(O)—, —OC(O)NH—, or —NHCO₂—;-   Z is a C₁₋₄ alkylidene chain;-   L is selected from the group consisting of —O—, —S—, —SO—, —SO₂—,    —N(R⁶)SO₂—SO₂N(R⁶)—, —N(R⁶)—, —CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—,    —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—, —N(R⁶)N(R⁶)—, —C(O)N(R⁶)—,    —OC(O)N(R⁶)—, —C(R⁶)₂—O—, —C(R⁶)₂—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,    —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —C(R⁶)₂N(R⁶)C(O)—,    —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—,    —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, and —C(R⁶)₂N(R⁶)CON(R⁶)—;-   R² and R^(2′) are independently selected from the group consisting    of —R and -T-W-R⁶, or R² and R^(2′) taken together with their    intervening atoms form a fused, 5-8 membered, unsaturated or    partially unsaturated ring having 0-3 ring heteroatoms selected from    the group consisting of nitrogen, oxygen, and sulfur, wherein each    substitutable ring carbon of said fused ring formed by R² and R^(2′)    is independently substituted by halo, oxo, —CN, —NO₂, R⁷, or -V-R⁶,    and each substitutable ring nitrogen of said ring formed by R² and    R^(2′) is independently substituted by —R⁴;-   R³ is selected from the group consisting of —R, -halo, —OR, —C(═O)R,    —CO₂R, —COCOR, —COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂,    —CON(R⁷)₂, —SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆    aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂,    —N(R⁷)SO₂N(R⁷)₂, —N(R⁴)SO₂R, and —OC(═O)N(R)₂;-   each R is independently hydrogen or an optionally substituted group    selected from the group consisting of C₁₋₆ aliphatic, C₆₋₁₀ aryl, a    heteroaryl ring having 5-10 ring atoms, and a heterocyclyl ring    having 5-10 ring atoms;-   each R⁴ is independently selected from the group consisting of —R⁷,    —COR⁷, —CO₂(optionally substituted C₁₋₆ aliphatic), —CON(R⁷)₂, and    —SO₂R⁷;-   each R⁵ is independently selected from the group consisting of —R,    halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR,    —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂    (optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂,    —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, and    —OC(═O)N(R⁴)₂;-   V is selected from the group consisting of —O—, —S—, —SO—, —SO₂—,    —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—, —CO₂—, —N(R⁶)CO—,    —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—, —N(R⁶)N(R⁶)—,    —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—,    —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —C(R⁶)₂N(R⁶)C(O)—,    —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—,    —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, and —C(R⁶)₂N(R⁶)CON(R⁶)—;-   W is selected from the group consisting of —C(R⁶)₂O—, —C(R⁶)₂S—,    —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—,    —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)OC(O)N(R⁶)—, C(R⁶)₂N(R⁶)CO—,    —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—,    —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, and —CON(R⁶)—;-   each R⁶ is independently selected from the group consisting of    hydrogen and an optionally substituted C₁₋₄ aliphatic group, or two    R⁶ groups on the same nitrogen atom may be taken together with the    nitrogen atom to form a 3-6 membered heterocyclyl or heteroaryl    ring;-   each R^(6′) is independently selected from the group consisting of    hydrogen and a C₁₋₄ aliphatic group, or two R^(6′) on the same    carbon atom are taken together to form a 3-8 membered carbocyclic    ring;-   each R^(6″) is independently selected from the group consisting of    hydrogen, a C₁₋₄ aliphatic group, halogen, optionally substituted    aryl, and optionally substituted heteroaryl, or two R⁶ on adjacent    carbon atoms are taken together to form a 5-7 membered carbocyclic    ring; and-   each R⁷ is independently selected from the group consisting of    hydrogen and an optionally substituted C₁₋₆ aliphatic group, or two    R⁷ on the same nitrogen are taken together with the nitrogen to form    a 5-8 membered heterocyclyl or heteroaryl ring.

In a preferred embodiment, the JAK-2 inhibitor is ENMD-2076. In apreferred embodiment, the JAK-2 inhibitor is(E)-N-(5-methyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-2-styrylpyrimidin-4-amine.In a preferred embodiment, the JAK-2 inhibitor is a compound of Formula(XLIV):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. The preparation of this compound is described in U.S.Pat. Nos. 8,153,630; 7,563,787; and, 8,114,870 and U.S. PatentApplication Publication Nos. 2008/0200485 A1; 2007/0142368 A1;2009/0264422 A1; 2011/0318393 A1; and, 2009/0029992 A1, the disclosuresof which are incorporated by reference herein. In an embodiment, theJAK-2 inhibitor is a compound described in U.S. Pat. Nos. 8,153,630;7,563,787; and, 8,114,870 and U.S. Patent Application Publication Nos.2008/0200485 A1; 2007/0142368 A1; 2009/0264422 A1; 2011/0318393 A1; and,2009/0029992 A1, the disclosures of which are incorporated by referenceherein.

In an embodiment, the JAK-2 inhibitor is a compound of Formula (XLV):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal,prodrug, tautomer or N-oxide thereof,wherein M is selected from a group D1 and a group D2:

and wherein:

-   (A) when M is a group D1:-   X is selected from O, NH and NCH₃;-   A is selected from a bond and a group NR₂ where R₂ is hydrogen or    methyl;-   E is selected from a bond, CH₂, CH(CN) and C(CH₃)₂;-   R₁ is selected from:-   (i) a cycloalkyl group of 3 to 5 ring members optionally substituted    by hydroxy, fluorine, amino, methylamino, methyl or ethyl;-   (ii) a saturated heterocyclic group of 4 to 6 ring members    containing 1 or 2 heteroatom ring members selected from O, N, S and    SO₂, the heterocyclic group being optionally substituted by    (C₁₋₄)alkyl, amino or hydroxy; but excluding unsubstituted    4-morpholinyl, unsubstituted tetrahydropyran-4-yl, unsubstituted    2-pyrrolidinyl, and unsubstituted and 1-substituted piperidine-4-yl;-   (iii) a 2,5-substituted phenyl group of the formula:

wherein (a) when X is NH or N—CH₃, R₃ is selected from chlorine andcyano;and (b) when X is O, R₃ is CN;

-   (iv) a group CR₆R₇R₈ wherein R₆ and R₇ are each selected from    hydrogen and methyl, and R₈ is selected from hydrogen, methyl,    (C₁₋₄)alkylsulphonylmethyl, hydroxymethyl and cyano;-   (v) a pyridazin-4-yl group optionally substituted by one or two    substituents selected from methyl, ethyl, methoxy and ethoxy;-   (vi) a substituted imidazothiazole group wherein the substituents    are selected from methyl, ethyl, amino, fluorine, chlorine, amino    and methylamino; and-   (vii) an optionally substituted 1,3-dihydro-isoindol-2-yl or    optionally substituted 2,3-dihydro-indol-1-yl group wherein the    optional substituents in each case are selected from halogen, cyano,    amino, C₁₋₄ mono- and dialkylamino, CONH₂ or CONH—(C₁₋₄)alkyl, C₁₋₄    alkyl and C₁₋₄ alkoxy wherein the C₁₋₄ alkyl and C₁₋₄ alkoxy groups    are optionally substituted by hydroxy, methoxy, or amino;-   (viii) 3-pyridyl optionally substituted by one or two substituents    selected from hydroxy, halogen, cyano, amino, C₁₋₄ mono- and    dialkylamino, CONH₂ or CONH—C₁₋₄ alkyl, C₁₋₄ alkyl and C₁₋₄ alkoxy    wherein the C₁₋₄ alkyl and C₁₋₄ alkoxy groups are optionally    substituted by hydroxy, methoxy, or amino, but excluding the    compounds 2-oxo-1,2-dihydro-pyridine-3-carboxylic acid    [3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide    and    2,6-dimethoxy-N-[3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-nicotinamide;-   (ix) thiomorpholine or an S-oxide or S,S-dioxide thereof optionally    substituted by one or two substituents selected from halogen, cyano,    amino, C₁₋₄ mono- and dialkylamino, CONH₂ or CONH—C₁₋₄ alkyl, C₁₋₄    alkyl and C₁₋₄ alkoxy wherein the C₁₋₄ alkyl and C₁₋₄ alkoxy groups    are optionally substituted by hydroxy, methoxy, or amino; and-   when E-A is NR₂, R₁ is additionally selected from:-   (x) 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,    2,4-difluorophenyl, 3,4-difluorophenyl, 2,5-difluorophenyl,    3,5-difluorophenyl, 2,4,6-trifluorophenyl, 2-methoxyphenyl,    5-chloro-2-methoxyphenyl, cyclohexyl, unsubstituted    4-tetrahydropyranyl and tert-butyl;-   (xi) a group NR₁₀R₁₁ where R₁₀ and R₁₁ are each C₁₋₄ alkyl or R₁₀    and R₁₁ are linked so that NR₁₀R₁₁ forms a saturated heterocyclic    group of 4 to 6 ring members optionally containing a second    heteroatom ring member selected from O, N, S and SO₂, the    heterocyclic group being optionally substituted by C₁₋₄ alkyl, amino    or hydroxy;-   (xii) pyridone optionally substituted by one or two substituents    selected from hydroxy, halogen, cyano, amino, C₁₋₄ mono- and    dialkylamino, CONH2, CONH—C₁₋₄ alkyl, C₁₋₄ alkyl and C₁₋₄ alkoxy    wherein the C₁₋₄ alkyl and C₁₋₄ alkoxy groups are optionally    substituted by hydroxy, methoxy, or amino;-   when E-A is C(CH₃)₂NR₂ or CH₂—NR₂, R₁ is additionally selected from:-   (xiii) unsubstituted 2-furyl and 2,6-difluorophenyl; and-   when E-A is C(CH3)₂NR₂, R₁ is additionally selected from:-   (xiv) unsubstituted phenyl; and-   when E is CH₂, R₁ is additionally selected from:-   (xv) unsubstituted tetrahydropyran-4-yl; and-   (B) when M is a group D2:-   A is selected from a bond and a group NR₂ where R₂ is hydrogen or    methyl;-   E is selected from a bond, CH₂, CH(CN) and C(CH₃)₂;-   R₁ is selected from:-   (xvi) a 2-substituted 3-furyl group of the formula:

wherein R₄ and R₅ are the same or different and are selected fromhydrogen and C₁₋₄ alkyl, or R₄ and R₅ are linked so that NR₄R₅ forms a5- or 6-membered saturated heterocyclic group optionally containing asecond heteroatom or group selected from O, NH, NMe, S or SO₂, the 5- or6-membered saturated ring being optionally substituted by hydroxy,fluorine, amino, methylamino, methyl or ethyl; (xvii) a 5-substituted2-furyl group of the formula:

wherein R₄ and R₅ are the same or different and are selected fromhydrogen and C₁₋₄ alkyl, or R₄ and R₅ are linked so that NR₄R₅ forms a5- or 6-membered saturated heterocyclic group optionally containing asecond heteroatom or group selected from O, NH, NMe, S or SO₂, the 5- or6-membered saturated heterocyclic group being optionally substituted byhydroxy, fluorine, amino, methylamino, methyl or ethyl;with the proviso that the compound is not5-piperidin-1-ylmethyl-furan-2-carboxylic acid[3-(5,6-dimethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;

-   (xviii) a group of the formula:

wherein R₉ is hydrogen, methyl, ethyl or isopropyl; G is CH, O, S, SO,SO₂ or NH and the group is optionally substituted by one, two or threesubstituents selected from C₁₋₄ hydrocarbyl, hydroxy, C₁₋₄hydrocarbyloxy, fluorine, amino, mono- and di-C₁₋₄ alkylamino andwherein the C₁₋₄ hydrocarbyl and C₁₋₄ hydrocarbyloxy groups are eachoptionally substituted by hydroxy, fluorine, amino, mono- or di-C₁₋₄alkylamino; and

-   (xix) a 3,5-disubstituted phenyl group of the formula:

wherein X is selected from O, NH and NCH₃; and

-   (C) when M is a group D1:    and X is O; A is a group NR₂ where R₂ is hydrogen; E is a bond; and    R₁ is 2,6-difluorophenyl; then the compound of the Formula (XLV) is    an acid addition salt selected from salts formed with an acid    selected from the group consisting of acetic, adipic, alginic,    ascorbic (e.g. L-ascorbic), aspartic (e.g. L-aspartic),    benzenesulphonic, benzoic, camphoric (e.g. (+) camphoric), capric,    caprylic, carbonic, citric, cyclamic, dodecanoate, dodecylsulphuric,    ethane-1,2-disulphonic, ethanesulphonic, fumaric, galactaric,    gentisic, glucoheptonic, D-gluconic, glucuronic (e.g. D-glucuronic),    glutamic (e.g. L-glutamic), α-oxoglutaric, glycolic, hippuric,    hydrochloric, isethionic, isobutyric, lactic (e.g. (+)-L-lactic and    (±)-DL-lactic), lactobionic, laurylsulphonic, maleic, malic,    (−)-L-malic, malonic, methanesulphonic, mucic, naphthalenesulphonic    (e.g. naphthalene-2-sulphonic), naphthalene-1,5-disulphonic,    nicotinic, oleic, orotic, oxalic, palmitic, pamoic, phosphoric,    propionic, sebacic, stearic, succinic, sulphuric, tartaric (e.g.    (+)-L-tartaric), thiocyanic, toluenesulphonic (e.g.    p-toluenesulphonic), valeric and xinafoic acids.

In a preferred embodiment, the JAK-2 inhibitor is AT-9283. In apreferred embodiment, the JAK-2 inhibitor is1-cyclopropyl-3-(3-(5-(morpholinomethyl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazol-4-yl)urea.In a preferred embodiment, the JAK-2 inhibitor is a compound of Formula(XLVI):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. The preparation of this compound is described in U.S.Pat. Nos. 8,399,442 and 7,977,477 and U.S. Patent ApplicationPublication Nos. 2010/0004232 A1; 2014/0010892 A1; 2011/0224203 A1; and,2007/0135477, the disclosures of which are incorporated by referenceherein. In an embodiment, the JAK-2 inhibitor is a compound described inU.S. Pat. Nos. 8,399,442 and 7,977,477 and U.S. Patent ApplicationPublication Nos. 2010/0004232 A1; 2014/0010892 A1; 2011/0224203 A1; and,2007/0135477, the disclosures of which are incorporated by referenceherein.

In an embodiment, the JAK-2 inhibitor is a compound of Formula (XLVII):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, wherein:

-   R¹ and R² are each independently selected from the group consisting    of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,    heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,    heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl,    heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl,    cycloalkylheteroalkyl, heterocycloalkylheteroalkyl,    heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl,    alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy,    cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy,    benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino,    arylamino, sulfonylamino, sulfinylamino, —COOH, —COR³, —COOR³,    —CONHR³, —NHCOR³, —NHCOOR³, —NHCONHR³, alkoxycarbonyl,    alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl,    arylsulfonyl, arylsulfinyl, aminosulfonyl, —SR³, R⁴S(O)R⁶—,    R⁴S(O)₂R⁶—, R⁴C(O)N(R⁵)R⁶—, R⁴SO₂N(R⁵)R⁶—, R⁴N(R⁵)C(O)R⁶—,    R⁴N(R⁵)SO₂R⁶—, R⁴N(R⁵)C(O)N(R⁵)R⁶— and acyl, each of which may be    optionally substituted;-   each R³, R⁴, and R⁵ is independently selected from the group    consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl,    cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl,    heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of    which may be optionally substituted;-   each R⁶ is independently selected from the group consisting of a    bond, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl,    heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl,    heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of    which may be optionally substituted;-   Z² is independently selected from the group consisting of a bond, O,    S, —N(R⁷)—, —N(R⁷)C₁₋₂alkyl-, and —C₁₋₂alkylN(R⁷)—;-   each R⁷ is independently selected from the group consisting of H,    alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl,    heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl,    heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of    which may be optionally substituted;-   Ar¹ and Ar² are each independently selected from the group    consisting of aryl and heteroaryl, each of which may be optionally    substituted;-   L is a group of formula:    —X¹—Y—X²—-   wherein X¹ is attached to Ar¹ and X² is attached to Ar², and wherein    X¹, X² and Y are selected such that the group L has between 5 and 15    atoms in the normal chain,-   X¹ and X² are each independently a heteroalkyl group containing at    least one oxygen atom in the normal chain,-   Y is a group of formula —CR^(a)═CR^(b)— or an optionally substituted    cycloalkyl group,-   wherein R^(a) and R^(b) are each independently selected from the    group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl,    heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,    cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl    and acyl, each of which may be optionally substituted, or-   R^(a) and R^(b) may be joined such that when taken together with the    carbon atoms to which they are attached they form a cycloalkenyl or    cycloheteroalkenyl group;-   or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal,    or prodrug thereof, or an N-oxide thereof.-   In certain embodiments Z² is selected from the group consisting of a    bond, —N(R⁷)—, and —S—. In one specific embodiment Z² is —N(R⁷)—. In    an even more specific embodiment Z² is —N(H)—.-   Ar¹ and Ar² are each independently selected from the group    consisting of aryl and heteroaryl and may be monocyclic, bicyclic or    polycyclic moieties. In certain embodiments each of Ar¹ and Ar² is a    monocyclic or bicyclic moiety. In certain embodiments each of Ar¹    and Ar² are a monocyclic moiety.

In certain embodiments Ar¹ is selected from the group consisting of:

-   wherein V¹, V², V³ and V⁴ are each independently selected from the    group consisting of N, and C(R¹⁰);-   W is selected from the group consisting of O, S and NR¹⁰;-   W¹ and W² are each independently selected from the group consisting    of N and CR¹⁰;-   wherein each R¹⁰ is independently selected from the group consisting    of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,    heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,    heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl,    heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl,    cycloalkylheteroalkyl, heterocycloalkylheteroalkyl,    heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl,    alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy,    cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy,    benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino,    arylamino, sulfonylamino, sulfinylamino, —COOH, —COR³, —COOR³,    —CONHR³, —NHCOR³, —NHCOOR³, —NHCONHR³, alkoxycarbonyl,    alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl,    arylsulfonyl, arylsulfinyl, aminosulfonyl, —SR³, R⁴S(O)R⁶—,    R⁴S(O)₂R⁶—, R⁴C(O)N(R⁵)R⁶—, R⁴SO₂N(R⁵)R⁶—, R⁴N(R⁵)C(O)R⁶—,    R⁴N(R⁵)SO₂R⁶—, R⁴N(R⁵)C(O)N(R⁵)R⁶— and acyl, each of which may be    optionally substituted,-   wherein R³, R⁴, R⁵ and R⁶ are as defined above.

In certain embodiments Ar¹ is selected from the group consisting of:

-   wherein V¹, V², V³, V⁴, W, W¹, W², R³, R⁴, R⁵ and R⁶ are as defined    above.

In yet an even further embodiment Ar¹ is selected from the groupconsisting of:

-   wherein each R¹⁰ is independently as defined above,-   k is an integer selected from the group consisting of 0, 1, 2, 3,    and 4; and-   n is an integer selected from the group consisting of 0, 1, and 2.

In yet an even further embodiment Ar¹ is selected from the groupconsisting of:

-   wherein R¹⁰ is as defined above.

In certain embodiments Ar¹ is selected from the group consisting of:

-   wherein each R¹⁰ is independently as defined above, and-   q is an integer selected from the group consisting of 0, 1 and 2.

In certain embodiments Ar¹ is selected from the group consisting of:

In certain embodiments Ar¹ is selected from the group consisting of:

In certain embodiments Ar² is selected from the group consisting of:

wherein V⁵, V⁶, V⁷ and V⁸ are independently selected from the groupconsisting of N, and C(R¹¹);wherein each R¹¹ is independently selected from the group consisting of:H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl,heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl,cycloalkylheteroalkyl, heterocycloalkylheteroalkyl,heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy,alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy,heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy,heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino,sulfonylamino, sulfinylamino, —COOH, —COR³, —COOR³, —CONHR³, —NHCOR³,—NHCOOR³, —NHCONHR³, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl,alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl,—SR³, R⁴S(O)R⁶—, R⁴S(O)₂R⁶—, R⁴C(O)N(R⁵)R⁶—, R⁴SO₂N(R⁵)R⁶—,R⁴N(R⁵)C(O)R⁶—, R⁴N(R⁵)SO₂R⁶—, R⁴N(R⁵)C(O)N(R⁵)R⁶— and acyl, each ofwhich may be optionally substituted.

In certain embodiments Ar² is selected from the group consisting of:

-   wherein each R¹¹ is independently as defined above-   o is an integer selected from the group consisting of 0, 1, 2, 3,    and 4; and-   p is an integer selected from the group consisting of 0, 1, 2, and    3.

In certain embodiments Ar² is selected from the group consisting of:

-   wherein each R¹¹ is as defined above.

In a further embodiment Ar² is selected from the group consisting of:

In an embodiment, the JAK-2 inhibitor is a compound of Formula (XLVIII):

-   or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal,    or prodrug thereof-   wherein R¹, R², R¹⁰, R¹¹, X¹, X², Y, k and o are as defined above.

In an embodiment, the JAK-2 inhibitor is a compound of Formula (XLIX):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof

-   wherein R¹, R², R¹⁰, R¹¹, X¹, X², Y, q and o are as defined above.

In an embodiment, the JAK-2 inhibitor is a compound of Formula (L):

-   or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal,    or prodrug thereof-   wherein R¹, R², R¹⁰, R¹¹, X¹, X², Y, q and o are as defined above.

In an embodiment, the JAK-2 inhibitor is a compound of Formula (LI):

-   or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal,    or prodrug thereof-   wherein R¹, R², R¹⁰, R¹¹, X¹, X², Y, q and o are as defined above.

In an embodiment, the JAK-2 inhibitor is a compound of Formula (LII):

-   or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal,    or prodrug thereof-   wherein R¹, R², R¹⁰, R¹¹, X¹, X², Y, q and o are as defined above.

In an embodiment, the JAK-2 inhibitor is a compound of Formula (LIII):

-   or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal,    or prodrug thereof-   wherein R¹, R², R¹⁰, R¹¹, X¹, X², Y, q and o are as defined above.

In embodiments where the JAK-2 inhibitor is a compound of Formulas(XLVII)-(LIII), X¹, X² and Y are chosen such that there are between 5and 15 atoms in the normal chain. In one embodiment, X¹, X² and Y arechosen such that there are between 6 and 15 atoms in the normal chain.In one specific embodiment, X¹, X² and Y are chosen such that there are7 atoms in the normal chain. In another specific embodiment, X¹, X² andY are chosen such that there are 8 atoms in the normal chain.

In embodiments where the JAK-2 inhibitor is a compound of Formulas(XLVII)-(LIII), X¹ and X² are each independently a heteroalkyl groupcontaining at least one oxygen atom in the normal chain. In certainembodiments X¹ is selected from the group consisting of: (a)—O(C₁₋₅)alkyl-, (b) —(C₁₋₅)alkylO—, and (c) —(C₁₋₅)alkylO(C₁₋₅)alkyl. Incertain embodiments X¹ is selected from the group consisting of: (a)—OCH₂— (b) —CH₂O—, (c) —OCH₂CH₂—, (d) —CH₂CH₂O—, (e) —CH₂OCH₂—, and (f)—CH₂CH₂OCH₂—. In one specific embodiment X¹ is —OCH₂—. In anotherspecific embodiment X¹ is —CH₂O—. In another specific embodiment X¹ is—OCH₂CH₂—. In another specific embodiment X¹ is —CH₂CH₂O—. In anotherspecific embodiment X¹ is —CH₂OCH₂—. In another specific embodiment X¹is —CH₂CH₂OCH₂—. In certain embodiments X² is selected from the groupconsisting of: (a) —O(C₁₋₅)alkyl-, (b) —(C₁₋₅)alkylO—, and (c)—(C₁₋₅)alkylO(C₁₋₅)alkyl. In certain embodiments X² is selected from thegroup consisting of: (a) —OCH₂— (b) —CH₂O—, (c) —OCH₂CH₂—, (d)—CH₂CH₂O—, (e) —CH₂OCH₂—, and (f) —CH₂CH₂OCH₂—. In one specificembodiment X² is —OCH₂—. In another specific embodiment X¹ is —CH₂O—. Inanother specific embodiment X² is —OCH₂CH₂—. In another specificembodiment X² is —CH₂CH₂O—. In another specific embodiment X² is—CH₂OCH₂—. In another specific embodiment X² is —CH₂CH₂OCH₂—.

In a preferred embodiment, the JAK-2 inhibitor is pacritinib. Pacritinibis also known as SB1518. In a preferred embodiment, the JAK-2 inhibitoris(E)-4⁴-(2-(pyrrolidin-1-yl)ethoxy)-6,11-dioxa-3-aza-2(4,2)-pyrimidina-1,4(1,3)-dibenzenacyclododecaphan-8-ene.In a preferred embodiment, the JAK-2 inhibitor is14,19-dioxa-5,7,27-triazatetracyclo[19.3.1.1^(2,6).1^(8,12)]heptacosa-1(25),2,4,6(27),8,10,12(26),16,21,23-decaene,11-[2-(1-pyrrolidinyl)ethoxy]-, (16E)-. In a preferred embodiment, theJAK-2 inhibitor is(16E)-11-[2-(pyrrolidin-1-yl)ethoxy]-14,19-dioxa-5,7,27-triazatetracyclo[19.3.1.1^(2,6).1^(8,12)]heptacosa-1(24),2,4,6,8,10,12(26),16,21(25),22-decaene.In an embodiment, the JAK-2 inhibitor is a compound of Formula (LIV):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. In an embodiment, the structure of Formula (LIV) may bea tautomeric form. The preparation of Formula (LIV) is described in U.S.Pat. Nos. 8,143,255; 8,153,632; and, 8,415,338 and U.S. PatentApplication Publication Nos. 2009/0258886 A1; 2012/0142680 A1;2012/0196855 A1; and 2013/0172338 A1, the disclosures of which areincorporated by reference herein. The preparation and properties of thisJAK-2 inhibitor are known to those of ordinary skill in the art, and forexample are described in: Hart, et al., SB1518, a novel macrocyclicpyrimidine-based JAK2 inhibitor for the treatment of myeloid andlymphoid malignancies, Leukemia 2011, 25, 1751-1759; Hart, et al.,Pacritinib (SB1518), a JAK2/FLT3 inhibitor for the treatment of acutemyeloid leukemia, Blood Cancer J., 2011, 1(11), e44; William, et al.,Discovery of the macrocycle11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene(SB1518), a potent Janus kinase 2/fms-like tyrosine kinase-3 (JAK2/FLT3)inhibitor for the treatment of myelofibrosis and lymphoma. J. Med. Chem.2011, 54, 4638-4658; Poulsen, et al. Structure-based design ofoxygen-linked macrocyclic kinase inhibitors: discovery of SB1518 andSB1578, potent inhibitors of Janus kinase 2 (JAK2) and Fms-like tyrosinekinase-3 (FLT3). J. Comput. Aided Mol. Des. 2012, 26, 437-450.

In an embodiment, the JAK-2 inhibitor is selected from the structuresdisclosed in U.S. Pat. Nos. 8,143,255; 8,153,632; and 8,415,338 and U.S.Patent Application Publication Nos. 2009/0258886 A1; 2012/0142680 A1;2012/0196855 A1; and 2013/0172338 A1, the disclosures of which areincorporated by reference herein.

In a preferred embodiment, the JAK-2 inhibitor is(E)-4⁴-(2-(pyrrolidin-1-yl)ethoxy)-6,11-dioxa-3-aza-2(4,2)-pyrimidina-1(2,5)-furana-4(1,3)-benzenacyclododecaphan-8-ene.In a preferred embodiment, the JAK-2 inhibitor is(9E)-15-(2-(pyrrolidin-1-yl)ethoxy)-7,12,25-trioxa-19,21,24-triaza-tetracyclo[18.3.1.1(2,5).1(14,18)]hexacosa-1(24),2,4,9,14(26),15,17,20,22-nonaene.In a preferred embodiment, the JAK-2 inhibitor is a compound of Formula(LIV-A):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. The preparation and properties of this JAK-2 inhibitorare known to those of ordinary skill in the art, and for example aredescribed in: Madan et al., SB1578, a novel inhibitor of JAK2, FLT3, andc-Fms for the treatment of rheumatoid arthritis, J. Immunol. 2012, 189,4123-4134 and William et al., Discovery of the macrocycle(9E)-15-(2-(pyrrolidin-1-yl)ethoxy)-7,12,25-trioxa-19,21,24-triaza-tetracyclo[18.3.1.1(2,5).1(14,18)]hexacosa-1(24),2,4,9,14(26),15,17,20,22-nonaene (SB1578), a potent inhibitor ofjanus kinase 2/fms-like tyrosine kinase-3 (JAK2/FLT3) for the treatmentof rheumatoid arthritis. J. Med. Chem. 2012, 55, 2623-2640.

In an embodiment, the JAK-2 inhibitor is a compound selected from thestructures disclosed in U.S. Pat. No. 8,349,851 and U.S. PatentApplication Publication Nos. 2010/0317659 A1, 2013/0245014, 2013/0296363A1, the disclosures of which are incorporated by reference herein. In anembodiment, the JAK-2 inhibitor is a compound of Formula (LV):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, wherein

-   R¹ and R² are selected from (i), (ii), (iii), (iv), and (v) as    follows:    (i) R¹ and R² together form ═O, ═S, ═NR⁹ or ═CR¹⁰R¹¹;    (ii) R¹ and R² are both —OR⁸, or R¹ and R², together with the carbon    atom to which they are attached, form dioxacycloalkyl;    (iii) R¹ is hydrogen or halo; and R² is halo; and    (iv) R¹ is alkyl, alkenyl, alkynyl, cycloalkyl or aryl, wherein the    alkyl, alkenyl, alkynyl, cycloalkyl and aryl is optionally    substituted with one or more substitutents selected from halo,    cyano, alkyl, —R^(x)OR^(w), —R^(x)S(O)_(q)R^(v), —R^(x)NR^(y)R^(z)    and —C(O)OR^(w); and R² is halo or —OR⁸; and    (v) R¹ is halo, deutero, —OR¹², —NR¹³R¹⁴, or —S(O)_(q)R¹⁵; and R² is    hydrogen, deutero, alkyl, alkenyl, alkynyl, cycloalkyl or aryl,    wherein the alkyl, alkenyl, alkynyl, cycloalkyl and aryl, is    optionally substituted with one or more substitutents selected from    halo, cyano, alkyl, —R^(x)OR^(w), —R^(x)S(O)_(q)R^(v) and    —R^(x)NR^(y)R^(z);-   R³ is hydrogen, halo, alkyl, cyano, haloalkyl, cycloalkyl,    cycloalkylalkyl, hydroxy or alkoxy;-   R⁴ and R⁵ are each independently hydrogen or alkyl;-   each R⁶ is independently selected from halo, alkyl, alkenyl,    alkynyl, haloalkyl, cycloalkyl, —R^(x)OR¹⁸, —R^(x)NR¹⁹R²⁰, and    —R^(x)S(O)_(q)R^(v);-   each R⁷ is independently halo, alkyl, haloalkyl or —R^(x)OR^(w);-   R⁸ is alkyl, alkenyl or alkynyl;-   R⁹ is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy or amino;-   R¹⁰ is hydrogen or alkyl;-   R¹¹ is hydrogen, alkyl, haloalkyl or —C(O)OR⁸;-   R¹² is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl,    heteroaryl, heteroaralkyl, —C(O)R^(v), —C(O)OR^(w) and    —C(O)NR^(y)R^(z), wherein the alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl,    heteroaryl and heteroaralkyl are each optionally substituted with    one or more substituents independently selected from halo, oxo,    alkyl, hydroxy, alkoxy, amino and alkylthio;-   R¹³ and R¹⁴ are selected as follows:    (i) R¹³ is hydrogen or alkyl; and R¹⁴ is selected from hydrogen,    alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,    heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkoxy,    —C(O)R^(v), —C(O)OR^(w), —C(O)NR^(y)R^(z) and —S(O)_(q)R^(v),    wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,    heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl and    heteroaralkyl are each optionally substituted with one or more    substituents independently selected from halo, oxo, alkyl, hydroxy,    alkoxy, amino and alkylthio; or    (ii) R¹³ and R¹⁴, together with the nitrogen atom to which they are    attached, form heterocyclyl or heteroaryl wherein the heterocyclyl    or heteroaryl is optionally substituted with one or more    substituents independently selected from halo, alkyl, hydroxy,    alkoxy, amino and alkylthio and wherein the heterocyclyl is also    optionally substituted with oxo;-   R¹⁵ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,    heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl,    heteroaralkyl, —C(O)NR^(y)R^(z) or —NR^(y)R^(z), wherein the alkyl,    alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,    heterocyclylalkyl, aryl, aralkyl, heteroaryl and heteroaralkyl are    each optionally substituted with one or more substituents    independently selected from halo, oxo, alkyl, hydroxy, alkoxy, amino    and alkylthio;-   R¹⁸ is hydrogen, alkyl, haloalkyl, hydroxy(C₂₋₆)alkyl, alkenyl,    alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,    heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl;    wherein R¹⁸ is optionally substituted with 1 to 3 groups Q¹, each Q¹    independently selected from alkyl, hydroxyl, halo, haloalkyl,    alkoxy, aryloxy, alkoxyalkyl, alkoxycarbonyl, alkoxysulfonyl,    hydroxycarbonyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,    haloaryl and amino;-   R¹⁹ and R²⁰ are selected as follows:-   (i) R¹⁹ and R²⁰ are each independently hydrogen or alkyl; or-   (ii) R¹⁹ and R²⁰, together with the nitrogen atom to which they are    attached, form a heterocyclyl or heteroaryl which is optionally    substituted with 1 to 2 groups each independently selected from    halo, alkyl, haloalkyl, hydroxyl and alkoxy;-   each R^(x) is independently alkylene or a direct bond;-   R^(v) is hydrogen, alkyl, alkenyl or alkynyl;-   R^(w) is independently hydrogen, alkyl, alkenyl, alkynyl or    haloalkyl;-   R^(y) and R^(z) are selected as follows:-   (i) R^(y) and R^(z) are each independently hydrogen, alkyl, alkenyl,    alkynyl, cycloalkyl or haloalkyl;-   (ii) R^(y) and R^(z), together with the nitrogen atom to which they    are attached, form a heterocyclyl or heteroaryl which is optionally    substituted with 1 to 2 groups each independently selected from    halo, alkyl, haloalkyl, hydroxyl and alkoxy;-   n is 0-4;-   p is 0-5; and-   each q is independently 0, 1 or 2.

In a preferred embodiment, the JAK-2 inhibitor is AC-410 (available fromAmbit Biosciences). In a preferred embodiment, the JAK-2 inhibitor is(S)-(4-fluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)methanol.In a preferred embodiment, the JAK-2 inhibitor is a compound of Formula(LVI):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. The preparation of racemic(4-fluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)methanolhydrochloride is described in Examples 3 and 12 of U.S. Pat. No.8,349,851, the disclosure of which is incorporated by reference herein.Other preparation methods known to one of skill in the art also may beused. The preparation of the compound of Formula (LVI) is also describedin the following paragraphs.

The preparation of(4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanoneis accomplished by the following two steps (A and B). Step A: To asolution of ethyl 4-chloroquinazoline-2-carboxylate (0.6 g, 2.53 mmol)in THF (6 mL) at −40° C., was added dropwise a 1 M solution of4-fluorophenylmagnesium bromide in THF (3 mL, 3.0 mmol, 1.2 eq). Themixture was stirred at −40° C. for 4 h. The reaction was quenched byadding 0.5 N HCl solution (5 mL) and the mixture was extracted withEtOAc (2×10 mL). The combined organic layers were washed with brine anddried over MgSO₄. The crude product was purified on a silica gel columnusing a mixture of EtOAc-hexanes as eluent.(4-chloroquinazoline-2-yl)(4-fluorophenyl)methanone was obtained as alight yellow solid (440 mg, 60%). ¹H NMR (300 MHz, DMSO-d6) δ 7.45-740(m, 2H), 8.07-8.03 (m, 1H), 8.17-8.13 (m, 2H), 8.23 (m, 2H), 8.42 (d,1H); LC-MS (ESI) m/z 287 (M+H)⁺. Step B: To a solution of(4-chloroquinazolin-2-yl)(4-fluorophenyl)methanone (84 mg, 0.30 mmol) inDMF (3 mL) were added DIEA (0.103 mL, 0.6 mmol) and5-methyl-1H-pyrazol-3-amine (88 mg, 0.9 mmol at rt. The reaction mixturewas heated at 40° C. overnight. The reaction was quenched by addingwater and the yellow precipitate was collected by filtration and washedwith water. The crude product was purified by silica gel chromatographyeluting with DCM/MeOH to give(4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone(30 mg, 29%). ¹H NMR (300 MHz, DMSO-d6) δ 2.19 (s, 3H), 6.54 (s, 1H),7.40 (m, 2H), 7.68 (t, 1H), 7.9-7.7 (m, 2H), 8.08 (m, 2H), 8.74 (d, 1H),10.66 (s, 1H), 12.20 (s, 1H); LC-MS (ESI) m/z 348 (M+H)⁺.

To a solution of4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone(60 mg, 0.172 mmol) in 1:1 MeOH/THF (10 mL) at 0° C., was added NaBH₄(64 mg, 1.69 mmol). The reaction mixture was stirred at 0° C. for 1.5 h.The reaction mixture was quenched by adding a few drops of acetone andconcentrated to dryness. The crude solid was purified on HPLC to afford(4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanol(18 mg, 30%); ¹H NMR (300 MHz, DMSO-d6) δ 2.25 (s, 3H), 5.67 (s, 1H),5.83 (bs, 1H), 6.40 (bs, 1H), 7.13 (m, 2H), 7.55-7.53 (m, 3H), 7.79 (s,2H), 8.57 (bs, 1H), 10.43 (s, 1H), 12.12 (bs, 1H); LC-MS (ESI) m/z 350(M+H)⁻.

To a suspension of(4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone(2.3 g) in 30% MeOH/DCM (60 mL) at 0° C. was added dropwise 4MHCl/1,4-dioxane (10 mL). After all solid material had dissolved, themixture was concentrated under reduced pressure, and to the residue wasadded 30% CH₃CN/H₂O (80 mL) and the mixture was sonicated until allsolid material had dissolved. The mixture was frozen and lyophilizedovernight to afford(4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanolhydrochloride (100%). ¹H NMR (300 MHz, DMSO-d6) δ 2.25 (s, 3H), 6.02 (s,1H), 6.20 (s, 1H), 7.27 (t, 2H), 7.60 (qt, 2H), 7.80 (t, 1H), 8.08 (t,1H), 8.23 (d, 1H), 8.83 (d, 1H), 12.16 (s, 1H), 14.51 (b, 1H); LC-MS(ESI) m/z 350 (M+H)⁺. The compound of Formula (LVI),(S)-(4-fluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)methanol,may be obtained from this preparation by chiral liquid chromatographicseparation of the enantiomers, or by other well known techniques forresolution of enantiomers, such as those described in: Eliel et al.,Stereochemistry of organic Compounds, Wiley-Interscience, New York,1994.

In a preferred embodiment, the JAK-2 inhibitor is(R)-(4-fluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)methanol,which is also known in the art to be active as a JAK-2 inhibitor. In apreferred embodiment, the JAK-2 inhibitor is racemic(4-fluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)methanol,which is also known in the art to be active as a JAK-2 inhibitor.

In some preferred embodiments, JAK-2 inhibitors having Formula (LV) orFormula (LVI) can be prepared, isolated, or obtained by any method knownto one of skill in the art, including, but not limited to, synthesisfrom a suitable optically pure precursor, asymmetric synthesis from anachiral starting material, or resolution of a racemic or enantiomericmixture, for example, chiral chromatography, recrystallization,resolution, diastereomeric salt formation, or derivatization intodiastereomeric adducts followed by separation.

A method for preparation of the compound of Formula (LVI) comprisesresolving racemic(4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanolwith chiral chromatography. In certain embodiments, the two individualenantiomers are separated using a chiral column, wherein the stationaryphase is silica gel coated with a chiral selector such astris-(3,5-dimethylphenyl)carbamoyl cellulose.

A method for preparation of the compound of Formula (LVI) comprises thestep of reducing the achiral ketone(4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone,prepared as described above or by other methods known to one of skill inthe art, with hydrogen in the present of a chiral catalyst. The achiralketone(4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanonemay be reduced to predominantly a single enantiomeric product with achiral reducing system of “type A” or “type B,” wherein type A and typeB differ from each other solely by having chiral auxiliaries of oppositechiralities. In certain embodiments, the chiral catalyst is [(S)—P-PhosRuCl₂ (S)-DAIPEN].

The reduction of the achiral ketone(4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanonein presence of a chiral catalyst may be carried out in isopropyl alcoholas a solvent. The reduction of achiral ketone(4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanonein the presence of a chiral catalyst is carried out in isopropyl alcoholand water mixture as a solvent. Isopropyl alcohol and water are used ina ratio of 1:1, 8:1 or 9:1. DMSO is used as a cosolvent in the reaction.Alternatively, DMSO is used in amounts of 10, 20 or 30% based on thetotal amount of isopropyl alcohol and water mixture. Alternatively,isopropyl alcohol, DMSO and water are used in a ratio of 1:1:1, 4:4:0.5,8:1:1, 47:47:6, 41:58:1, 44:50:6, or 18:79:3. Alternatively, isopropylalcohol, DMSO and water are used in a ratio of 41:58:1. Alternatively,isopropyl alcohol, and DMSO are used in a ratio of 1:1. Alternatively,the reduction is carried out in presence of a base, such as potassiumhydroxide, potassium tert butoxide and others. Alternatively, the baseis used in 2-15 mol %, in one embodiment, 2 mol %, 5 mol %, 10 mol %,12.5 mol % or 15 mol %. Alternatively, the reduction is carried out at atemperature of 40-80° C., in one embodiment, 40° C., 50° C., 60° C., 70°C. or 80° C. Alternatively, the reduction is carried out at atemperature of 70° C. Alternatively, the reduction is carried out at apressure of 4 bar to 30 bar, in one embodiment, 4, 5, 10, 15, 20, 25 or30 bar. Alternatively, the reduction is carried out at a pressure of 4bar. Alternatively, the catalyst loading in the reaction is 100/1,250/1, 500/1, 1000/1, 2000/1, 3000/1, 4000/1, 5000/1, 7000/1, 10,0000/1or 20,000/1. In certain embodiments, the catalyst loading in thereaction is 2000/1 or 4000/1.

A method for preparation of the compound of Formula (LVI)comprises thestep of reducing the achiral ketone(4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanonewith a ketoreductase (e.g., alcohol dehydrogenase). See Moore, et al.,Acc. Chem. Res. 2007, 40, 1412-1419; Daussmann, et al., Engineering inLife Sciences 2006, 6, 125-129; Schlummer, et al., Specialty ChemicalsMagazine 2008, 28, 48-49; Osswald, et al., Chimica Oggi 2007,25(Suppl.), 16-18; and Kambourakis, et al., PharmaChem 2006, 5(9), 2-5.

An alternative method for preparation of the compound of Formula (LVI)comprises the step of reducing the achiral ketone(4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanonewith a reducing reagent (e.g., borane or borohydride reagents) in thepresence of a chiral catalyst. In certain embodiments, the reducingagent is borane or a borohydride reagent. In certain embodiments, thechiral catalyst is a chiral oxazaborolidine. Cory, et al., TetrahedronLetters 1996, 37, 5675; Cho, Chem. Soc. Rev. 2009, 38, 443.

Another method for preparation of the compound of Formula (LVI)comprises the step of reducing the achiral ketone(4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanonevia asymmetric hydrosilylation, as described in U.S. Patent ApplicationPublication No. 2008/0269490, the disclosure of which is specificiallyincorporated herein by reference.

Another method for preparation of the compound of Formula (LVI)comprises the step of reducing the achiral ketone(4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanonevia transfer hydrogenation catalyzed by an iridium complex, as describedin Malacea, et al., Coord. Chem. Rev. 2010, 254, 729-752.

The starting materials used in the synthesis of the compound of Formula(LVI) provided herein are either commercially available or can beprepared by a method known to one of skill in the art. For example, theachiral ketone(4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanonecan be prepared according to the methods described in U.S. Pat. No.8,349,851, issued Jan. 8, 2013, and U.S. Pat. No. 8,703,943, issued Apr.22, 2014, the disclosures of which are incorporated herein by referencein their entireties.

In an embodiment, the JAK-2 inhibitor is a JAK-2 inhibitor described inU.S. Patent Application Publication No. US 2013/0225614 A1, thedisclosure of which are specifically incorporated herein by reference.In an embodiment, the JAK-2 inhibitor is a compound of Formula (LV-A):

-   or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal,    or prodrug thereof, wherein-   A is azolyl other than pyrazolyl;-   R¹ and R² are selected from (i), (ii), (iii), (iv) and (v) as    follows:-   (i) R¹ and R² together form =0, ═S, ═NR⁹ or ═CR¹⁰R^(n);-   (ii) R¹ and R² are both —OR⁸, or R¹ and R², together with the carbon    atom to which they are attached, form cycloalkyl or heterocyclyl    wherein the cycloalkyl is substituted with one to four substituents    selected from halo, deutero, alkyl, haloalkyl, —OR, —N(R)₂, and    —S(O)_(q)R and wherein the heterocyclyl contains one to two    heteroatoms wherein each heteroatom is independently selected from    O, NR²⁴, S, S(O) and S(O)₂;-   (iii) R¹ is hydrogen or halo; and R² is halo;-   (iv) R¹ is alkyl, alkenyl, alkynyl, cycloalkyl or aryl, wherein the    alkyl, alkenyl, alkynyl, cycloalkyl and aryl are each optionally    substituted with one to four substitutents selected from halo,    deutero, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cyano,    =0, ═N—OR²¹, —R^(x)OR²¹, —R^(X)N(R²²)₂, —R^(x)S(O)_(q)R²³, —C(O)R²¹,    —C(O)OR²¹ and —C(O)N(R²²)₂; and-   (v) R¹ is halo, deutero, —OR¹², —NR¹³R¹⁴, or —S(O)_(q)R¹⁵, and R² is    hydrogen, deutero, alkyl, alkenyl, alkynyl, cycloalkyl or aryl,    wherein the alkyl, alkenyl, alkynyl, cycloalkyl and aryl are each    optionally substituted with one to four substitutents selected from    halo, cyano, alkyl, —R^(x)OR^(w), —R^(x)S(O)_(q)R^(v) and    —R^(x)NR^(y)R^(z);-   R³ is hydrogen, deutero, halo, alkyl, cyano, haloalkyl,    deuteroalkyl, cycloalkyl, cycloalkylalkyl, hydroxy or alkoxy;-   R⁵ is hydrogen or alkyl; each R⁶ is independently selected from    halo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, —R^(x)OR¹⁸,    —R^(X)NR¹⁹R²⁰, and —R^(x)S(O)_(q)R^(v);-   each R⁷ is independently halo, alkyl, haloalkyl or —R^(x)OR^(w);-   R is alkyl, alkenyl or alkynyl;-   R⁹ is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy or amino;-   R¹⁰ is hydrogen or alkyl;-   R¹¹ is hydrogen, alkyl, haloalkyl or —C(O)OR⁸;-   R¹² is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl,    heteroaryl, heteroaralkyl, —C(O)R^(v), —C(O)OR^(w) and    —C(O)NR^(y)R^(z), wherein the alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl,    heteroaryl and heteroaralkyl are each optionally substituted with    one or more, in one embodiment, one to four, in one embodiment, one    to three, in one embodiment, one, two or three, substituents    independently selected from halo, oxo, alkyl, hydroxy, alkoxy, amino    and alkylthio;-   R¹³ and R¹⁴ are selected as follows:    -   (i) R¹³ is hydrogen or alkyl; and R¹⁴ is selected from hydrogen,        alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,        heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl,        heteroaralkyl, alkoxy, —C(O)R^(v), —C(O)OR^(w), —C(O)NR^(y)R^(z)        and —S(O)_(q)R^(v), wherein the alkyl, alkenyl, alkynyl,        cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,        aryl, aralkyl, heteroaryl and heteroaralkyl are each optionally        substituted with one or more, in one embodiment, one to four, in        one embodiment, one to three, in one embodiment, one, two or        three, substituents independently selected from halo, oxo,        alkyl, hydroxy, alkoxy, amino and alkylthio; or    -   (ii) R¹³ and R¹⁴, together with the nitrogen atom to which they        are attached, form heterocyclyl or heteroaryl wherein the        heterocyclyl or heteroaryl are substituted with one or more, in        one embodiment, one to four, in one embodiment, one to three, in        one embodiment, one, two or three, substituents independently        selected from halo, alkyl, hydroxy, alkoxy, amino and alkylthio        and wherein the heterocyclyl is optionally substituted with oxo;        R¹⁵ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,        heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl,        heteroaralkyl, —C(O)NR^(y)R^(z) or —NR^(y)R^(z), wherein the        alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,        heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl and        heteroaralkyl are each optionally substituted with one or more,        in one embodiment, one to four, in one embodiment, one to three,        in one embodiment, one, two or three, substituents independently        selected from halo, oxo, alkyl, hydroxy, alkoxy, amino and        alkylthio;-   R¹⁸ is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl,    cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,    aralkyl, heteroaryl or heteroarylalkyl; wherein R¹⁸ is optionally    substituted with 1 to 3 groups Q¹, each Q¹ independently selected    from alkyl, hydroxyl, halo, oxo, haloalkyl, alkoxy, aryloxy,    alkoxyalkyl, alkoxycarbonyl, alkoxysulfonyl, carboxyl, cycloalkyl,    heterocyclyl, aryl, heteroaryl, haloaryl and amino;-   R¹⁹ and R²⁰ are selected as follows:    -   (i) R¹⁹ and R²⁰ are each independently hydrogen or alkyl; or    -   (ii) R¹⁹ and R²⁰, together with the nitrogen atom to which they        are attached, form a heterocyclyl or heteroaryl which are each        optionally substituted with 1 to 2 groups each independently        selected from halo, oxo, alkyl, haloalkyl, hydroxyl and alkoxy;-   R²¹ is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl or cycloalkyl;-   each R²² is independently hydrogen, alkyl, alkenyl, alkynyl,    haloalkyl or cycloalkyl; or both R²², together with the nitrogen    atom to which they are attached, form a heterocyclyl optionally    substituted with oxo;-   R²³ is alkyl, alkenyl, alkynyl or haloalkyl;-   R²⁴ is hydrogen or alkyl;-   each R^(x) is independently alkylene or a direct bond;-   R^(v) is hydrogen, alkyl, alkenyl or alkynyl;-   R^(w) is independently hydrogen, alkyl, alkenyl, alkynyl or    haloalkyl;-   R^(y) and R^(z) are selected as follows:    -   (i) R^(y) and R^(z) are each independently hydrogen, alkyl,        alkenyl, alkynyl, cycloalkyl or haloalkyl; or    -   (ii) R^(y) and R^(z), together with the nitrogen atom to which        they are attached, form a heterocyclyl or heteroaryl which are        optionally substituted with 1 to 2 groups each independently        selected from halo, alkyl, haloalkyl, hydroxyl and alkoxy;-   n is 0-4;-   p is 0-5;-   each q is independently 0, 1 or 2; and-   r is 1-3.

In an embodiment, the JAK-2 inhibitor of Formula (LV-A) is a compound ofFormula (LV-B):

-   or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal,    or prodrug thereof, wherein-   A is imidazolyl, oxazolyl, thiazolyl, thiadiazolyl, or triazolyl;-   R³ is hydrogen, alkyl, haloalkyl or cycloalkyl;-   each R⁶ is independently selected from halo, alkyl, alkenyl,    alkynyl, haloalkyl, cycloalkyl, —R^(x)OR¹⁸, —R^(X)NR¹⁹R²⁰, and    —R^(x)S(O)_(q)R^(v);-   R⁷ is halo;-   R¹⁸ is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl,    cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,    aralkyl, heteroaryl or heteroarylalkyl; wherein R¹⁸ is optionally    substituted with 1 to 3 groups Q¹, each Q¹ independently selected    from alkyl, hydroxyl, halo, oxo, haloalkyl, alkoxy, aryloxy,    alkoxyalkyl, alkoxycarbonyl, alkoxysulfonyl, carboxyl, cycloalkyl,    heterocyclyl, aryl, heteroaryl, haloaryl and amino;-   R¹⁹ and R²⁰ are selected as follows:    -   (i) R¹⁹ and R²⁰ are each independently hydrogen or alkyl; or    -   (ii) R¹⁹ and R²⁰, together with the nitrogen atom to which they        are attached, form a heterocyclyl or heteroaryl which are each        optionally substituted with 1 to 2 groups each independently        selected from halo, oxo, alkyl, haloalkyl, hydroxyl and alkoxy;-   each R^(x) is independently alkylene or a direct bond;-   R^(v) is hydrogen, alkyl, alkenyl or alkynyl;-   R^(y) and R^(z) are selected as follows:    -   (i) R^(y) and R^(z) are each independently hydrogen, alkyl,        alkenyl, alkynyl, cycloalkyl or haloalkyl; or    -   (ii) R^(y) and R^(z), together with the nitrogen atom to which        they are attached, form a heterocyclyl or heteroaryl which are        optionally substituted with 1 to 2 groups each independently        selected from halo, alkyl, haloalkyl, hydroxyl and alkoxy;-   n is 0-3;-   each q is independently 0, 1 or 2; and-   r is 1-3.

In a preferred embodiment of the JAK-2 inhibitor of Formula (LV-A) or(LV-B), R³ is hydrogen or alkyl.

In a preferred embodiment of the JAK-2 inhibitor of Formula (LV-A) or(LV-B), A is imidazolyl, oxazolyl, thiazolyl, thiadiazolyl, ortriazolyl.

In a preferred embodiment of the JAK-2 inhibitor of Formula (LV-A) or(LV-B), R⁷ is fluro.

In a preferred embodiment, the JAK-2 inhibitor of Formula (LV-A) is acompound of Formula (LV-C):

-   or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal,    or prodrug thereof, where-   R¹ and R² are selected as follows:    -   (i) R¹ and R² together form =0;    -   (ii) R¹ and R², together with the carbon atom to which they are        attached, form dioxacycloalkyl or cycloalkyl wherein the        cycloalkyl is substituted with one to four substituents selected        from halo, deutero, alkyl, cycloalkyl, heterocyclyl, aryl,        heteroaryl, cyano, =0, and hydroxy;    -   (iii) R¹ is hydrogen or halo; and R² is halo;    -   (iv) R¹ is alkyl, and R² is hydrogen, alkyl, halo, hydroxy or        alkoxy; or    -   (v) R¹ is halo, hydroxy or alkoxy; and R² is hydrogen or alkyl;-   R³ is hydrogen, alkyl or cycloalkyl,-   R⁴ is hydrogen or alkyl;-   R⁵ is hydrogen or alkyl;-   R⁷ is halo; and-   n is 0-3.

In a preferred embodiment of the JAK-2 inhibitor of Formula (LV-C), n is0.

In an embodiment, JAK-2 inhibitor of Formula (LV-A) has the structure ofFormula (LV-D):

-   or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal,    or prodrug thereof, where-   R¹ and R² are selected as follows:-   (i) R^(L) and R² together form =0;-   (ii) R¹ and R², together with the carbon atom to which they are    attached, form dioxacycloalkyl or cycloalkyl wherein the cycloalkyl    is substituted with one to four substituents selected from halo,    deutero, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cyano,    =0, and hydroxy;-   (iii) R¹ is hydrogen or halo; and R² is halo;-   (iv) R¹ is alkyl, and R² is hydrogen, alkyl, halo, hydroxy or    alkoxy; or-   (v) R¹ is halo, hydroxy or alkoxy; and R² is hydrogen or alkyl; R³    is hydrogen, alkyl or cycloalkyl,-   R⁵ is hydrogen or alkyl;-   R⁷ is halo; and-   n is 0-3.

In a preferred embodiment of the JAK-2 inhibitor of Formula (LV-D), n is0.

In a preferred embodiment, JAK-2 inhibitor of Formula (LV-D) is selectedfrom the group consisting of:

-   (4-fluorophenyl)(4-((1-methyl-1H-imidazol-4-yl)amino)quinazolin-2-yl)methanol;    (4-((1H-imidazol-4-yl)amino)quinazolin-2-yl)(4-fluorophenyl)methanol;-   (4-fluorophenyl)(4-(thiazol-4-ylamino)quinazolin-2-yl)methanol;-   (4-fluorophenyl)(4-((5-methylthiazol-2-yl)amino)quinazolin-2-yl)methanol;    and    2-(difluoro(4-fluorophenyl)methyl)-N-(1-methyl-1H-imidazol-4-yl)quinazolin-4-amine,    -   or a pharmaceutically acceptable salt, solvate, hydrate,        cocrystal, or prodrug thereof.

In an embodiment, the JAK-2 inhibitor is a compound of Formula (LVII):

-   or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal,    or prodrug thereof, wherein:-   R¹ is selected from hydrogen, hydroxy, amino, mercapto, C₁₋₆alkyl,    C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆ alkoxy, C₁₋₆alkanoyloxy,    N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,    C₁₋₆alkylsulphonylamino, 3-5-membered carbocyclyl or 3-5-membered    heterocyclyl; wherein R¹ may be optionally substituted on carbon by    one or more R⁶; and wherein if said heterocyclyl contains an —NH—    moiety that nitrogen may be optionally substituted by a group    selected from R⁷;-   R² and R³ are independently selected from hydrogen, halo, nitro,    cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,    C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆ alkanoyl,    C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂-amino, C₁₋₆    alkanoylamino, N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl,    C₁₋₆alkylS(O)_(a) wherein a is 0 to 2, C₁₋₆alkoxycarbonyl,    N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆ alkyl)₂sulphamoyl,    (C₁₋₆alkyl)₂N—S(O)₂—NH—, (C₁₋₆alkyl)NH—S(O)₂—NH—, NH₂—S(O)₂—NH—,    (C₁₋₆alkyl)₂N—S(O)₂—N(C₁₋₆alkyl)-,    (C₁₋₆alkyl)NH—S(O)₂—N(C₁₋₆alkyl)-, NH₂—S(O)₂—N(C₁₋₆alkyl)-,    N—(C₁₋₆alkyl)-N—(C₁₋₆alkylsulphonyl)amino, C₁₋₆ alkylsulphonylamino,    carbocyclyl-R¹⁹— or heterocyclyl-R²¹; wherein R² and R³    independently of each other may be optionally substituted on carbon    by one or more R⁸; and wherein if said heterocyclyl contains an —NH—    moiety that nitrogen may be optionally substituted by a group    selected from R⁹;-   R⁴ is selected from cyano, carboxy, carbamoyl, C₁₋₆alkyl,    C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkanoyl, N—(C₁₋₆alkyl)carbamoyl,    N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkoxycarbonyl, carbocyclyl or    heterocyclyl; wherein R⁴ may be optionally substituted on carbon by    one or more R¹⁰; and wherein if said heterocyclyl contains an —NH—    moiety that nitrogen may be optionally substituted by a group    selected from R¹¹;-   R⁵ is selected from halo, nitro, cyano, hydroxy, amino, carboxy,    carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl,    C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy,    N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,    N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a)    wherein a is 0 to 2, C₁₋₆alkoxycarbonyl, N—(C₁₋₆ alkyl)sulphamoyl,    N,N—(C₁₋₆alkyl)₂sulphamoyl, C₁₋₆alkylsulphonylamino, carbocyclyl or    heterocyclyl; wherein R⁵ may be optionally substituted on carbon by    one or more R¹²; and wherein if said heterocyclyl contains an —NH—    moiety that nitrogen may be optionally substituted by a group    selected from R¹³;-   n=0, 1, 2 or 3; wherein the values of R⁵ may be the same or    different;-   R⁶, R⁸, R¹⁰ and R¹² are independently selected from halo, nitro,    cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,    C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆ alkanoyl,    C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₆    alkanoylamino, N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl,    C₁₋₆alkylS(O)_(a) wherein a is 0 to 2, C₁₋₆alkoxycarbonyl,    N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆ alkyl)₂sulphamoyl,    C₁₋₆alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R⁶,    R⁸, R¹⁰ and R¹² independently of each other may be optionally    substituted on carbon by one or more R¹⁴; and wherein if said    heterocyclyl contains an —NH— moiety that nitrogen may be optionally    substituted by a group selected from R¹⁵;-   R⁷, R⁹, R¹¹, R¹³ and R¹⁵ are independently selected from C₁₋₆alkyl,    C₁₋₆alkanoyl, C₁₋₆alkylsulphonyl, C₁₋₆alkoxycarbonyl, carbamoyl,    N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)carbamoyl, benzyl,    benzyloxycarbonyl, benzoyl and phenylsulphonyl; wherein R⁷, R⁹, R¹¹,    R¹³ and R¹⁵ independently of each other may be optionally    substituted on carbon by on or more R¹⁶;-   R¹⁴ and R¹⁶ are independently selected from halo, nitro, cyano,    hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl,    C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆ alkanoyl,    C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₆    alkanoylamino, N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl,    C₁₋₆alkylS(O)_(a) wherein a is 0 to 2, C₁₋₆alkoxycarbonyl,    N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆ alkyl)₂sulphamoyl,    C₁₋₆alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R¹⁴    and R¹⁶ independently of each other may be optionally substituted on    carbon by one or more R¹⁷; and wherein if said heterocyclyl contains    an —NH— moiety that nitrogen may be optionally substituted by a    group selected from R¹⁸;-   R¹⁷ is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy,    trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl,    methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino,    ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino,    acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl,    N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,    N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl,    ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl,    ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl,    N,N-dimethylsulphamoyl, N,N-diethyl sulphamoyl or    N-methyl-N-ethylsulphamoyl; and-   R¹⁹ and R²¹ are independently selected from a direct bond, —O—,    —N(R²²)—, —C(O)—, —N(R²³)C(O)—, —C(O)N(R²⁴)—, —S(O)_(s)—,    —SO₂N(R²⁵)— or —N(R²⁶)SO₂—; wherein R²², R²³, R²⁴, R²⁵ and R²⁶ are    independently selected from hydrogen or C₁₋₆alkyl and s is 0-2;-   R¹⁸ is selected from C₁₋₆alkyl, C₁₋₆alkanoyl, C₁₋₆alkylsulphonyl,    C₁₋₆alkoxycarbonyl, carbamoyl, N—(C₁₋₆alkyl)carbamoyl,    N,N—(C₁₋₆alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and    phenylsulphonyl;-   or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal,    or prodrug thereof.

In an embodiment, the JAK-2 inhibitor is a compound of Formula (LVII),wherein:

-   R¹ is selected from hydrogen, hydroxy, amino, mercapto, C₁₋₆alkyl,    C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆ alkoxy, C₁₋₆alkanoyloxy,    N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,    C₁₋₆alkylsulphonylamino, 3-5-membered carbocyclyl or 3-5-membered    heterocyclyl; wherein R¹ may be optionally substituted on carbon by    one or more R⁶; and wherein if said heterocyclyl contains an —NH—    moiety that nitrogen may be optionally substituted by a group    selected from R⁷;-   R² and R³ are independently selected from hydrogen, halo, nitro,    cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,    C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆ alkanoyl,    C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₆    alkanoylamino, N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl,    C₁₋₆alkylS(O)_(a) wherein a is 0 to 2, C₁₋₆alkoxycarbonyl,    N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆ alkyl)₂sulphamoyl,    C₁₋₆alkylsulphonylamino, carbocyclyl-R¹⁹— or heterocyclyl-R²¹—;    wherein R² and R³ independently of each other may be optionally    substituted on carbon by one or more R⁸; and wherein if said    heterocyclyl contains an —NH— moiety that nitrogen may be optionally    substituted by a group selected from R⁹;-   R⁴ is selected from cyano, carboxy, carbamoyl, C₁₋₆alkyl,    C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkanoyl, N—(C₁₋₆alkyl)carbamoyl,    N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkoxycarbonyl, carbocyclyl or    heterocyclyl; wherein R⁴ may be optionally substituted on carbon by    one or more R¹⁰; and wherein if said heterocyclyl contains an —NH—    moiety that nitrogen may be optionally substituted by a group    selected from R¹¹;-   R⁵ is selected from halo, nitro, cyano, hydroxy, amino, carboxy,    carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl,    C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy,    N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,    N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a)    wherein a is 0 to 2, C₁₋₆alkoxycarbonyl, N—(C₁₋₆ alkyl)sulphamoyl,    N,N—(C₁₋₆alkyl)₂sulphamoyl, C₁₋₆alkylsulphonylamino, carbocyclyl or    heterocyclyl; wherein R⁵ may be optionally substituted on carbon by    one or more R²; and wherein if said heterocyclyl contains an —NH—    moiety that nitrogen may be optionally substituted by a group    selected from R¹³;-   n=0, 1, 2 or 3; wherein the values of R⁵ may be the same or    different;-   R⁶, R⁸, R¹⁰ and R¹² are independently selected from halo, nitro,    cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,    C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl,    C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino,    C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,    N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,    C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆    alkyl)₂sulphamoyl, C₁₋₆alkylsulphonylamino, carbocyclyl or    heterocyclyl; wherein R⁶, R⁸, R¹⁰ and R¹² independently of each    other may be optionally substituted on carbon by one or more R¹⁴;    and wherein if said heterocyclyl contains an —NH— moiety that    nitrogen may be optionally substituted by a group selected from R¹⁵;-   R⁷, R⁹, R¹¹, R¹³ and R¹⁵ are independently selected from C₁₋₆alkyl,    C₁₋₆alkanoyl, C₁₋₆alkylsulphonyl, C₁₋₆alkoxycarbonyl, carbamoyl,    N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆ alkyl)carbamoyl, benzyl,    benzyloxycarbonyl, benzoyl and phenylsulphonyl; wherein R⁷, R⁹, R¹¹,    R¹³ and R¹⁵ independently of each other may be optionally    substituted on carbon by on or more R¹⁶;-   R¹⁴ and R¹⁶ are independently selected from halo, nitro, cyano,    hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl,    C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆ alkanoyl,    C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₆    alkanoylamino, N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl,    C₁₋₆alkylS(O)_(a) wherein a is 0 to 2, C₁₋₆alkoxycarbonyl,    N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆ alkyl)₂sulphamoyl,    C₁₋₆alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R¹⁴    and R¹⁶ independently of each other may be optionally substituted on    carbon by one or more R¹⁷; and wherein if said heterocyclyl contains    an —NH— moiety that nitrogen may be optionally substituted by a    group selected from R¹⁸;-   R¹⁷ is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy,    trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl,    methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino,    ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino,    acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl,    N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,    N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl,    ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl,    ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl,    N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl or    N-methyl-N-ethylsulphamoyl; and-   R¹⁹ and R²¹ are independently selected from —O—, —N(R²²)—, —C(O)—,    —N(R²³)C(O)—, —C(O)N(R²⁴)—, —S(O)_(s)—, —SO₂N(R²⁵)— or —N(R²⁶)SO₂—;    wherein R²², R²³, R²⁴, R²⁵ and R²⁶ are independently selected from    hydrogen or C₁₋₆alkyl and s is 0-2;-   R⁸ is selected from C₁₋₆alkyl, C₁₋₆alkanoyl, C₁₋₆alkylsulphonyl,    C₁₋₆alkoxycarbonyl, carbamoyl, N—(C₁₋₆alkyl)carbamoyl,    N,N—(C₁₋₆alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and    phenylsulphonyl;-   or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal,    or prodrug thereof.

In an embodiment, the JAK-2 inhibitor is a compound of Formula (LVII),wherein:

-   R¹ is selected from hydrogen, hydroxy, amino, mercapto, C₁₋₆alkyl,    C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆ alkoxy, C₁₋₆alkanoyloxy,    N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,    C₁₋₆alkylsulphonylamino, 3-5-membered carbocyclyl or 3-5-membered    heterocyclyl; wherein R¹ may be optionally substituted on carbon by    one or more R⁶; and wherein if said heterocyclyl contains an —NH—    moiety that nitrogen may be optionally substituted by a group    selected from R⁷;-   R² and R³ are independently selected from hydrogen, halo, nitro,    cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,    C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆ alkanoyl,    C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₆    alkanoylamino, N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl,    C₁₋₆alkylS(O)_(a) wherein a is 0 to 2, C₁₋₆alkoxycarbonyl,    N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆ alkyl)₂sulphamoyl,    N—(C₁₋₆alkyl)-N—(C₁₋₆alkylsulphonyl)amino, C₁₋₆alkylsulphonylamino,    carbocyclyl-R¹⁹— or heterocyclyl-R²¹—; wherein R² and R³    independently of each other may be optionally substituted on carbon    by one or more R⁸; and wherein if said heterocyclyl contains an —NH—    moiety that nitrogen may be optionally substituted by a group    selected from R⁹;-   R⁴ is selected from cyano, carboxy, carbamoyl, C₁₋₆alkyl,    C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkanoyl, N—(C₁₋₆alkyl)carbamoyl,    N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkoxycarbonyl, carbocyclyl or    heterocyclyl; wherein R⁴ may be optionally substituted on carbon by    one or more R¹⁰; and wherein if said heterocyclyl contains an —NH—    moiety that nitrogen may be optionally substituted by a group    selected from R¹¹;-   R⁵ is selected from halo, nitro, cyano, hydroxy, amino, carboxy,    carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl,    C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy,    N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,    N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a)    wherein a is 0 to 2, C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl,    N,N—(C₁₋₆alkyl)₂sulphamoyl, C₁₋₆alkylsulphonylamino, carbocyclyl or    heterocyclyl; wherein R⁵ may be optionally substituted on carbon by    one or more R¹²; and wherein if said heterocyclyl contains an —NH—    moiety that nitrogen may be optionally substituted by a group    selected from R¹³;-   n=0, 1, 2 or 3; wherein the values of R⁵ may be the same or    different;-   R⁶, R⁸, R¹⁰ and R¹² are independently selected from halo, nitro,    cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,    C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl,    C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₆    alkanoylamino, N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl,    C₁₋₆alkylS(O)_(a) wherein a is 0 to 2, C₁₋₆alkoxycarbonyl,    N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆ alkyl)₂sulphamoyl,    C₁₋₆alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R⁶,    R⁸, R¹⁰ and R¹² independently of each other may be optionally    substituted on carbon by one or more R¹⁴; and wherein if said    heterocyclyl contains an —NH— moiety that nitrogen may be optionally    substituted by a group selected from R¹⁵;-   R⁷, R⁹, R¹¹, R¹³ and R¹⁵ are independently selected from    (C₁₋₆)alkyl, (C₁₋₆)alkanoyl, (C₁₋₆)alkylsulphonyl,    (C₁₋₆)alkoxycarbonyl, carbamoyl, N—((C₁₋₆)alkyl)carbamoyl,    N,N—((C₁₋₆)alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and    phenylsulphonyl; wherein R⁷, R⁹, R¹¹, R¹³ and R¹⁵ independently of    each other may be optionally substituted on carbon by on or more    R¹⁶;-   R¹⁴ and R¹⁶ are independently selected from halo, nitro, cyano,    hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,    (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl, (C₁₋₆)alkoxy,    (C₁₋₆)alkanoyl, (C₁₋₆)alkanoyloxy, N—((C₁₋₆)alkyl)amino,    N,N—((C₁₋₆)alkyl)₂amino, (C₁₋₆)alkanoylamino,    N—((C₁₋₆)alkyl)carbamoyl, N,N—((C₁₋₆)alkyl)₂carbamoyl,    (C₁₋₆)alkylS(O)_(a) wherein a is 0 to 2, (C₁₋₆)alkoxycarbonyl,    N—((C₁₋₆)alkyl)sulphamoyl, N,N—((C₁₋₆)alkyl)₂sulphamoyl,    (C₁₋₆)alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R¹⁴    and R¹⁶ independently of each other may be optionally substituted on    carbon by one or more R¹⁷; and wherein if said heterocyclyl contains    an —NH— moiety that nitrogen may be optionally substituted by a    group selected from R¹⁸;-   R¹⁷ is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy,    trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl,    methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino,    ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino,    acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl,    N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,    N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl,    ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl,    ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl,    N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl or    N-methyl-N-ethylsulphamoyl; and-   R¹⁹ and R²¹ are independently selected from a direct bond, —O—,    —N(R²²)—, —C(O)—, —N(R²³)C(O)—, —C(O)N(R²⁴)—, —S(O)_(s)—,    —SO₂N(R²⁵)— or —N(R²⁶)SO₂—; wherein R²², R²³, R²⁴, R²⁵ and R²⁶ are    independently selected from hydrogen or (C₁₋₆)alkyl and s is 0-2;-   R¹⁸ is selected from (C₁₋₆)alkyl, (C₁₋₆)alkanoyl,    (C₁₋₆)alkylsulphonyl, (C₁₋₆)alkoxycarbonyl, carbamoyl,    N—((C₁₋₆)alkyl)carbamoyl, N,N—((C₁₋₆)alkyl)carbamoyl, benzyl,    benzyloxycarbonyl, benzoyl and phenylsulphonyl;-   or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal,    or prodrug thereof.

Particular values of the variable groups contained in Formula (LVII) areas follows. Such values may be used, where appropriate, with any of thedefinitions, claims or embodiments defined hereinbefore or hereinafterin relation to compounds of Formula (LVII).

-   R¹ is selected from (C₁₋₆)alkyl, (C₁₋₆)alkoxy, 3-5-membered    carbocyclyl, and N,N—((C₁₋₆)alkyl)₂amino, wherein R¹ may be    optionally substituted on carbon by one or more R⁶; and wherein R⁶    is halo,-   R¹ is (C₁₋₆)alkoxy or 3-5-membered carbocyclyl.-   R¹ is selected from (C₁₋₆)alkyl, (C₁₋₆)alkoxy or 3-5-membered    carbocyclyl.-   R¹ is (C₁₋₆)alkyl or (C₁₋₆)alkoxy.-   R¹ is 3-5 membered carbocyclyl.-   R¹ is N,N((C₁₋₆)alkyl)₂amino.-   R¹ is (C₁₋₆)alkyl.-   R¹ is (C₁₋₄)alkyl.-   R¹ is (C₁₋₆)alkoxy.-   R¹ is selected from methyl, methoxy, trifluoroethoxy, isopropoxy,    cyclopropyl, and N,N-dimethylamino;-   R¹ is isopropoxy or cyclopropyl.-   R¹ is methyl, methoxy, isopropoxy or cyclopropyl.-   R¹ is selected from methyl, methoxy, isopropoxy, N,N-dimethylamino,    and cyclopropyl.-   R¹ is isopropoxy.-   R¹ is methyl.-   R¹ is ethyl.-   R¹ is selected from methyl, ethyl, propyl, and butyl.-   R¹ is selected from (C₁₋₄)alkyl, (C₁₋₄)alkoxy, and cyclopropyl.-   R¹ is methoxy.-   R¹ is cyclopropyl. R¹ is N,N-dimethylamino.-   R² is selected from hydrogen, halo, nitro, and (C₁₋₆)alkyl, wherein    R² may be optionally substituted on carbon by one or more R⁸; and    wherein R⁸ is halo.-   R² is selected from hydrogen, chloro, fluoro, bromo, nitro, and    trifluoromethyl.-   R² is halo.-   R² is (C₁₋₆)alkyl, wherein R² may be optionally substituted on    carbon by one or more R⁸; and wherein R⁸ is halo.-   R² and R³ are independently selected from hydrogen, halo, nitro,    cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,    (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl, (C₁₋₆)alkoxy,    (C₁₋₆)alkanoyl, (C₁₋₆)alkanoyloxy, N—((C₁₋₆)alkyl)amino,    N,N—((C₁₋₆)alkyl)₂amino, (C₁₋₆)alkanoylamino,    N—((C₁₋₆)alkyl)carbamoyl, N,N—((C₁₋₆)alkyl)₂carbamoyl,    (C₁₋₆)alkylS(O)_(a) wherein a is 0 to 2, (C₁₋₆)alkoxycarbonyl,    N—((C₁₋₆)alkyl)sulphamoyl, N,N—((C₁₋₆)alkyl)₂sulphamoyl,    (C₁₋₆)alkylsulphonylamino, carbocyclyl-R¹⁹— or heterocyclyl-R²¹—;    wherein R² and R³ independently of each other may be optionally    substituted on carbon by one or more R⁸; and wherein if said    heterocyclyl contains an —NH— moiety that nitrogen may be optionally    substituted by a group selected from R⁹.-   R² and R³ are independently selected from hydrogen, halo, nitro,    cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,    (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl, (C₁₋₆)alkoxy,    (C₁₋₆)alkanoyl, (C₁₋₆)alkanoyloxy, N—((C₁₋₆)alkyl)amino,    N,N—((C₁₋₆)alkyl)₂amino, (C₁₋₆)alkanoylamino,    N—((C₁₋₆)alkyl)carbamoyl, N,N—((C₁₋₆)alkyl)₂carbamoyl,    (C₁₋₆)alkylS(O)_(a) wherein a is 0 to 2, (C₁₋₆)alkoxycarbonyl, N-(    )C₁₋₆alkyl)sulphamoyl, N,N—((C₁₋₆)alkyl)₂sulphamoyl,    N—((C₁₋₆)alkyl)-N—((C₁₋₆)alkylsulphonyl)amino,    (C₁₋₆)alkylsulphonylamino, carbocyclyl-R¹⁹— or heterocyclyl-R²¹—;    wherein R² and R³ independently of each other may be optionally    substituted on carbon by one or more R⁸; and wherein if said    heterocyclyl contains an —NH— moiety that nitrogen may be optionally    substituted by a group selected from R⁹.-   R² and R³ are independently selected from hydrogen, halo,    N—((C₁₋₆)alkyl)-N—((C₁₋₆)alkylsulphonyl)amino, or heterocyclyl-R²¹—;    wherein R²¹ is a direct bond.-   R² and R³ are independently selected from hydrogen and halo.-   R² and R³ are independently selected from hydrogen and chloro.-   R² and R³ are independently selected from hydrogen, fluoro, chloro,    bromo, N-methyl-N-mesylamino and morpholino.-   R² is halo and R³ is hydrogen.-   R² is chloro and R³ is hydrogen.-   R² is chloro or fluoro and R³ is hydrogen. R³ is selected from    hydrogen, halo, cyano,    N—((C₁₋₆)alkyl)-N—((C₁₋₆)alkylsulphonyl)amino, (C₁₋₆)alkyl,    ((C₁₋₆)alkyl)₂N—S(O)₂—N((C₁₋₆)alkyl)-, and heterocyclyl-R²¹—,    wherein R³ may be optionally substituted on carbon by one or more    R⁸; wherein R⁸ is halo; and wherein R²¹ is a bond.-   R³ is hydrogen.-   R³ is halo.-   R³ is selected from N—((C₁₋₆)alkyl)-N—((C₁₋₆)alkylsulphonyl)amino    and ((C₁₋₆)alkyl)₂N—S(O)₂—N((C₁₋₆)alkyl)-.-   R³ is selected from heterocyclyl-R²¹—, wherein R³ may be optionally    substituted on carbon by one or more R⁵; wherein R⁵ is halo; and    wherein R²¹ is a bond.-   R³ is selected from hydrogen, chloro, cyano, trifluoromethyl,    (CH₃)₂N—S(O)₂—N(CH₃)—, N-methyl-N-mesylamino, and morpholino.-   R³ is (CH₃)₂N—S(O)₂—N(CH₃)—.-   R³ is N-methyl-N-mesylamino,-   R³ is morpholino.-   R⁴ is (C₁₋₆)alkyl.-   R⁴ is methyl.-   R⁵ is halo.-   R⁵ is fluoro.-   n=1.-   R¹⁹ and R²¹ are independently selected from —O—, —N(R²²)—, —C(O)—,    —N(I²³)C(O)—, —C(O)N(R²⁴)—, —S(O)_(s)—, —SO₂N(R²⁵)— or —N(R²⁶)SO₂—;    wherein R²², R²³, R²⁴, R²⁵ and R²⁶ are independently selected from    hydrogen or (C₁₋₆)alkyl and s is 0-2.-   Therefore in a further aspect of the invention there is provided a    compound of Formula (LVII) (as depicted herein above) wherein:-   R¹ is selected from (C₁₋₆)alkyl, (C₁₋₆)alkoxy or 3-5-membered    carbocyclyl;-   R¹ and R³ are independently selected from hydrogen, halo,    N—((C₁₋₆)alkyl)-N—((C₁₋₆)alkylsulphonyl)amino, or heterocyclyl-R²¹—;-   R⁴ is (C₁₋₆)alkyl;-   R⁵ is halo;-   n=1;-   R²¹ is a direct bond;-   or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal,    or prodrug thereof.

Therefore, in an embodiment of the invention, the JAK-2 inhibitor is acompound of Formula (LVII) wherein:

-   R¹ is (C₁₋₆)alkoxy;-   R² and R³ are independently selected from hydrogen and halo;-   R⁴ is (C₁₋₆)alkyl;-   R⁵ is halo;-   n=1;-   or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal,    or prodrug thereof.

Therefore, in an embodiment of the invention, the JAK-2 inhibitor is acompound of Formula (LVII) wherein:

-   R¹ is methyl, methoxy, isopropoxy or cyclopropyl;-   R² and R³ are independently selected from hydrogen, fluoro, chloro,    bromo, N-methyl-N-mesylamino and morpholino;-   R⁴ is methyl;-   R⁵ is fluoro; and-   n=1;-   or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal,    or prodrug thereof.

Therefore, in an embodiment of the invention, the JAK-2 inhibitor is acompound of Formula (LVII) wherein:

-   R¹ is selected from (C₁₋₆)alkyl, (C₁₋₆)alkoxy, 3-5-membered    carbocyclyl, and N,N—((C₁₋₆)alkyl)₂amino, wherein R¹ may be    optionally substituted on carbon by one or more R⁶;-   R² is selected from hydrogen, halo, nitro, and (C₁₋₆)alkyl, wherein    R² may be optionally substituted on carbon by one or more R⁸;-   R³ is selected from hydrogen, halo, cyano,    N—((C₁₋₆)alkyl)-N—((C₁₋₆)alkylsulphonyl)amino, (C₁₋₆)alkyl,    ((C₁₋₆)alkyl)₂N—S(O)₂—N((C₁₋₆)alkyl)-, and heterocyclyl-R²¹—,    wherein R³ may be optionally substituted on carbon by one or more    R⁸;-   R⁴ is (C₁₋₆)alkyl;-   R⁵ is halo;-   R⁶ is halo;-   R⁸ is halo;-   R²¹ is a bond; and-   n=1;-   or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal,    or prodrug thereof.

Therefore, in an embodiment of the invention, the JAK-2 inhibitor is acompound of Formula (LVII) wherein:

-   R¹ is selected from methyl, methoxy, trifluoroethoxy, isopropoxy,    cyclopropyl, and N,N-dimethylamino;-   R² is selected from hydrogen, chloro, fluoro, bromo, nitro, and    trifluoromethyl;-   R³ is selected from hydrogen, chloro, cyano, trifluoromethyl,    (CH₃)₂N—S(O)₂—N(CH₃)—, N-methyl-N-mesylamino, and morpholino;-   R⁴ is methyl;-   R⁵ is fluoro; and-   n is 1;-   or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal,    or prodrug thereof.

Therefore, in an embodiment of the invention, the JAK-2 inhibitor is acompound of Formula (LVII) wherein:

-   R¹ is selected from (C₁₋₆)alkoxy, wherein R¹ may be optionally    substituted on carbon by one or more R⁶;-   R² is selected from hydrogen and halo;-   R³ is selected from hydrogen, halo, and heterocyclyl-R²¹—;-   R⁴ is (C₁₋₆)alkyl;-   R⁵ is halo;-   R⁶ is halo;-   R²¹ is a bond;-   n is 1;-   or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal,    or prodrug thereof.

Therefore, in an embodiment of the invention, the JAK-2 inhibitor is acompound of Formula (LVII) wherein:

-   R¹ is selected from (C₁₋₄)alkyl, (C₁₋₄)alkoxy, and cyclopropyl;-   R² is selected from hydrogen, halo, nitro, and (C₁₋₆)alkyl, wherein    R² may be optionally substituted on carbon by one or more R⁸;-   R³ is selected from hydrogen, halo, cyano,    N—((C₁₋₆)alkyl)-N—((C₁₋₆)alkylsulphonyl)amino, (C₁₋₆)alkyl,    ((C₁₋₆)alkyl)₂N—S(O)₂—N((C₁₋₆)alkyl)-, and heterocyclyl-R²¹—,    wherein R³ may be optionally substituted on carbon by one or more    R⁸;-   R⁴ is (C₁₋₆)alkyl;-   R⁵ is halo;-   R⁶ is halo;-   R⁸ is halo;-   R²¹ is a bond; and-   n=1;-   or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal,    or prodrug thereof.

In a preferred embodiment, the JAK-2 inhibitor is AZD-1480. In apreferred embodiment, the JAK-2 inhibitor is(S)-5-chloro-N²-(1-(5-fluoropyrimidin-2-yl)ethyl)-N⁴-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine.In a preferred embodiment, the JAK-2 inhibitor has the chemicalstructure shown in Formula (LVIII):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. The preparation of this compound is described in U.S.Pat. No. 8,088,784 and U.S. Patent Application Publication Nos.2008/0287475 A1; 2010/0160325 A1; and, 2012/0071480 A1, the disclosuresof which are incorporated by reference herein. In an embodiment, theJAK-2 inhibitor is selected from the compounds described in U.S. Pat.No. 8,088,784 and U.S. Patent Application Publication Nos. 2008/0287475A1; 2010/0160325 A1; and, 2012/0071480 A1, the disclosures of which areincorporated by reference herein.

In an embodiment, the JAK-2 inhibitor is a compound of Formula (LIX):

-   or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal,    or prodrug thereof, wherein:-   R¹ and R² are independently selected from hydrogen, halo, nitro,    cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl,    mercapto, sulphamoyl, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆    alkoxy, C₁₋₆ alkanoyl, C₁₋₆ alkanoyloxy, N—(C₁₋₆alkyl)amino,    N,N—(C₁₋₆ alkyl)₂-amino, C₁₋₆ alkanoylamino, N—(C₁₋₆    alkyl)carbamoyl, N,N—(C₁₋₆ alkyl)₂-carbamoyl, C₁₋₆ alkylS(O)_(a)    wherein a is 0 to 2, C₁₋₆ alkoxycarbonyl, N—(C₁₋₆ alkyl)sulphamoyl,    N,N—(C₁₋₆ alkyl)₂sulphamoyl, C₁₋₆ alkylsulphonylamino, carbocyclyl    or heterocyclyl; wherein R¹ and R² independently of each other may    be optionally substituted on carbon by one or more R⁶; and wherein    if said heterocyclyl contains an —NH— moiety that nitrogen may be    optionally substituted by a group selected from R⁷;-   one of X¹, X², X³ and X⁴ is ═N—, the other three are independently    selected from ═CR⁸—, ═CR⁹— and ═CR¹⁰—;-   R³ is hydrogen or optionally substituted C₁₋₆ alkyl; wherein said    optional substituents are selected from one or more R¹¹;-   R⁴ and R³⁴ are independently selected from hydrogen, halo, nitro,    cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl,    mercapto, sulphamoyl, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆    alkoxy, C₁₋₆ alkanoyl, C₁₋₆ alkanoyloxy, N—(C₁₋₆ alkyl)amino,    N,N—(C₁₋₆ alkyl)₂amino, C₁₋₆ alkanoylamino, N—(C₁₋₆ alkyl)carbamoyl,    N,N—(C₁₋₆ alkyl)₂carbamoyl, C₁₋₆ alkylS(O)_(a) wherein a is 0 to 2,    C₁₋₆ alkoxycarbonyl, N—(C₁₋₆ alkyl)sulphamoyl, N,N—(C₁₋₆    alkyl)₂sulphamoyl, C₁₋₆ alkylsulphonylamino, carbocyclyl or    heterocyclyl; wherein R⁴ and R³⁴ may be independently optionally    substituted on carbon by one or more R¹²; and wherein if said    heterocyclyl contains an —NH— moiety that nitrogen may be optionally    substituted by a group selected from R¹³;-   A is a direct bond or C₁₋₂alkylene; wherein said C₁₋₂alkylene may be    optionally substituted by one or more R¹⁴;-   Ring C is carbocyclyl or heterocyclyl; wherein if said heterocyclyl    contains an —NH— moiety that nitrogen may be optionally substituted    by a group selected from R¹⁵;-   R⁵ is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy,    amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₆ alkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkanoyl, C₁₋₆ alkanoyloxy,    N—(C₁₋₆ alkyl)amino, N,N—(C₁₋₆ alkyl)₂amino, C₁₋₆ alkanoylamino,    N—(C₁₋₆ alkyl)carbamoyl, N,N—(C₁₋₆ alkyl)₂carbamoyl, C₁₋₆    alkylS(O)_(a) wherein a is 0 to 2, C₁₋₆ alkoxycarbonyl, N—(C₁₋₆    alkyl)sulphamoyl, N,N—(C₁₋₆ alkyl)₂sulphamoyl, C₁₋₆    alkylsulphonylamino, carbocyclyl-R³⁷— or heterocyclyl-R³⁸—; wherein    R⁵ may be optionally substituted on carbon by one or more R¹⁶; and    wherein if said heterocyclyl contains an —NH— moiety that nitrogen    may be optionally substituted by a group selected from R¹⁷;-   n is 0, 1, 2 or 3; wherein the values of R⁵ may be the same or    different;-   R⁸, R⁹ and R¹⁰ are independently selected from hydrogen, halo,    nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl,    mercapto, sulphamoyl, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆    alkoxy, C₁₋₆ alkanoyl, C₁₋₆ alkanoyloxy, N—(C₁₋₆ alkyl)amino,    N,N—(C₁₋₆ alkyl)₂amino, C₁₋₆ alkanoylamino, N—(C₁₋₆ alkyl)carbamoyl,    N,N—(C₁₋₆ alkyl)₂carbamoyl, C₁₋₆ alkylS(O)_(a) wherein a is 0 to 2,    C₁₋₆ alkoxycarbonyl, N—(C₁₋₆ alkyl)sulphamoyl, N,N—(C₁₋₆    alkyl)₂sulphamoyl, C₁₋₆ alkylsulphonylamino, carbocyclyl-R²⁵— or    heterocyclyl-R²⁶—; wherein R⁸, R⁹ and R¹⁰ independently of each    other may be optionally substituted on carbon by one or more R¹⁸;    and wherein if said heterocyclyl contains an —NH— moiety that    nitrogen may be optionally substituted by a group selected from R¹⁹;-   R⁶, R¹¹, R¹², R¹⁴, R¹⁶ and R¹⁸ are independently selected from halo,    nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl,    mercapto, sulphamoyl, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆    alkoxy, C₁₋₆ alkanoyl, C₁₋₆ alkanoyloxy, N—(C₁₋₆ alkyl)amino,    N,N—(C₁₋₆ alkyl)₂amino, C₁₋₆ alkanoylamino, N—(C₁₋₆ alkyl)carbamoyl,    N,N—(C₁₋₆ alkyl)₂carbamoyl, C₁₋₆ alkylS(O)_(a) wherein a is 0 to 2,    C₁₋₆ alkoxycarbonyl, N—(C₁₋₆ alkyl)sulphamoyl, N,N—(C₁₋₆    alkyl)₂sulphamoyl, C₁₋₆ alkylsulphonylamino, carbocyclyl-R²⁷— or    heterocyclyl-R²⁸—; wherein R⁶, R¹¹, R¹², R¹⁴, R¹⁶ and R¹⁸    independently of each other may be optionally substituted on carbon    by one or more R²⁰; and wherein if said heterocyclyl contains an    —NH— moiety that nitrogen may be optionally substituted by a group    selected from R²¹;-   R⁷, R¹³, R¹⁵, R¹⁷, R¹⁹ and R²¹ are independently selected from C₁₋₆    alkyl, C₁₋₆ alkanoyl, C₁₋₆ alkylsulphonyl, C₁₋₆ alkoxycarbonyl,    carbamoyl, N—(C₁₋₆ alkyl)carbamoyl, N,N—(C₁₋₆ alkyl)carbamoyl,    benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl; wherein R⁷,    R¹³, R¹⁵, R¹⁷, R¹⁹ and R²¹ independently of each other may be    optionally substituted on carbon by on or more R²²;-   R²⁰ and R²² are independently selected from halo, nitro, cyano,    hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto,    sulphamoyl, C₁₋₃alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆    alkanoyl, C₁₋₆ alkanoyloxy, N—(C₁₋₆ alkyl)amino, N,N—(C₁₋₆    alkyl)₂amino, C₁₋₆ alkanoylamino, N—(C₁₋₆ alkyl)carbamoyl, N,N—(C₁₋₆    alkyl)₂carbamoyl, C₁₋₆ alkylS(O)_(a) wherein a is 0 to 2, C₁₋₆    alkoxycarbonyl, N—(C₁₋₆ alkyl)sulphamoyl, N,N—(C₁₋₆    alkyl)₂sulphamoyl, C₁₋₆ alkylsulphonylamino, C₁₋₆    alkylsulphonyl-N—(C₁₋₆ alkyl)amino, carbocyclyl-R³⁵— or    heterocyclyl-R³⁶—; wherein R²⁰ and R²² independently of each other    may be optionally substituted on carbon by one or more R²³; and    wherein if said heterocyclyl contains an —NH— moiety that nitrogen    may be optionally substituted by a group selected from R²⁴;-   R²⁵, R²⁶, R²⁷, R²⁸, R³⁵, R³⁶, R³⁷ and R³⁸ are independently selected    from a direct bond, —O—, —N(R²⁹)—, —C(O)—, —N(R³⁰)C(O)—,    —C(O)N(R³¹)—, —S(O)_(s)—, —NH═CH—, —SO₂N(R³²)— or —N(R³³)SO₂—;    wherein R²⁹, R³⁰, R³¹, R³² and R³³ are independently selected from    hydrogen or C₁₋₆ alkyl and s is 0-2;-   R²³ is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy,    trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl,    methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino,    ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino,    acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl,    N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,    N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl,    ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl,    ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl,    N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl, N-methyl-N-ethyl    sulphamoyl or phenyl; and-   R²⁴ is selected from C₁₋₆ alkyl, C₁₋₆ alkanoyl, C₁₋₆ alkylsulphonyl,    C₁₋₆ alkoxycarbonyl, carbamoyl, N—(C₁₋₆ alkyl)carbamoyl, N,N—(C₁₋₆    alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and    phenylsulphonyl;-   or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal,    or prodrug thereof.

In a preferred embodiment, the JAK-2 inhibitor is(S)-5-fluoro-2-((1-(4-fluorophenyl)ethyl)amino)-6-((5-methyl-1H-pyrazol-3-yl)amino)nicotinonitrile.In a preferred embodiment, the JAK-2 inhibitor is a compound of Formula(LX):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. The preparation of this compound is described in U.S.Pat. No. 8,324,252 and U.S. Patent Application Publication Nos.2008/0139561 A1 and 2013/0090358 A1, the disclosures of which areincorporated by reference herein. In an embodiment, the JAK-2 inhibitoris selected from the compounds described in U.S. Pat. No. 8,324,252 andU.S. Patent Application Publication Nos. 2008/0139561 A1 and2013/0090358 A1, the disclosures of which are incorporated by referenceherein.

In an embodiment, the JAK-2 inhibitor is a compound of Formula (LXII):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, or a stereoisomer thereof, wherein:

-   D is CH or N;-   E is CH or N;-   X is CH₂, NR₄, O or S;-   U is CH or N;-   V is CH or N;-   Y is CH or N;-   Z is CH or N;-   R1 is NR₅R₆, CR5R₆R₇, SR₅ or OR₅;-   R₂ is (C═O)OH, (C═O)NH₂, (C═O)NHR₄ or heterocyclyl;-   R₃ is    -   (a) hydrogen;    -   (b) C₁₋₆ alkyl, which is optionally substituted with halo,        hydroxyl, amino, phenyl, heterocyclyl, C₁₋₆ alkyl or R₁₀;    -   (c) C₂₋₆ alkenyl, which is optionally substituted with halo,        hydroxyl, amino, phenyl, heterocyclyl, C₁₋₆ alkyl or R₄;    -   (d) C₃₋₁₀ cycloalkyl, which is optionally substituted with C₁₋₆        alkyl, OR₄, NR₈R₄, phenyl (which is optionally substituted with        C₁₋₆ alkyl, OR₄ or NR₈R₄), halo, R₁₀ or heterocyclyl;    -   (e) —(CO)R₈;    -   (f) —(CO)—NR₈R₉;    -   (g) C₄₋₁₀ heterocyclyl, which is optionally substituted on        either the carbon or the heteroatom with C1-6 alkyl, halo, R₁₀,        OR₄, NR₈R₄, phenyl (which is optionally substituted with C1-6        alkyl, OR₄ or NR₈R₄), —(CO)R₈ or —(CO)—NR₈R₉;    -   (h) OR₄;    -   (i) NR₈R₄;    -   (j) halo;    -   (k) Aryl, which is optionally substituted with one or more        groups selected from C₁₋₆ alkyl (which is optionally substituted        with one to three halo), halo or R₁₀;    -   (l) Heteroaryl, which is optionally substituted with one or more        groups selected from C₁₋₆ alkyl (which is optionally substituted        with one to three halo), halo or R₁₀;    -   (m) O-aryl, which is optionally substituted with one or more        groups selected from C₁₋₆ alkyl, halo or R₁₀;    -   (n)O—C₁₋₆ alkyl, which is optionally substituted with C₁₋₆ alky,        halo or R₁₀; or    -   (o) L-A-R₁₀;-   R₄ is    -   (a) hydrogen;    -   (b) C₁₋₆ alkyl, which is optionally substituted with halo,        hydroxyl, amino, aryl or heterocyclyl;    -   (c) C₃₋₁₀ cycloalkyl, which is optionally substituted with C₁₋₆        alkyl, OR₁₁, NR₈R₁₁, phenyl (which is optionally substituted        with C₁₋₆ alkyl, OR₁₁ or NR₈R₁₁), heterocyclyl, aryl or        heteroaryl;    -   (d) —(CO)R₈;    -   (e) —(CO)—NR₈R₉;    -   (f) C₄₋₁₀ heterocyclyl, which is optionally substituted on        either the carbon or the heteroatom with C₁₋₆ alkyl, OR₁₁,        NR₈R₁₁, phenyl (which is optionally substituted with C₁₋₆ alkyl,        OR₁₁ or NR₈R₁₁), heterocyclyl, —(CO)R₈ or —(CO)—NR₈R₉;    -   (g) OR₁₁;    -   (h) NR₈R₁₁;    -   (i) Aryl, which is optionally substituted with one to five halo        or R₁₀;    -   (j) Heteroaryl (wherein the heteroaryl has 5 or 6 members in        which 1, 2, 3, or 4 of the atoms is a heteroatom selected from        N, S and O), which is optionally substituted with one to five        halo or R₁₀;-   R₅ is    -   (a) hydrogen;    -   (b) C₁₋₈ alkyl, which is optionally substituted with halo,        hydroxyl, amino, aryl, cycloalkyl or heterocyclyl;    -   (c) C₃₋₁₀ cycloalkyl, which is optionally substituted with C₁₋₆        alkyl, (C₁₋₆ alkyl)aryl, (C₁₋₆ alkyl)OR₉, OR₄, NR₈R₄, phenyl        (which is optionally substituted with C₁₋₆ alkyl, OR₄, NR₈R₄,        heterocyclyl, —(CO)R8 or —(CO)—NR₈R₉);    -   (d) —(CO)R₈;    -   (e) —(CO)—NR₈R₉;    -   (f) C₁₋₆ alkyl(C═O)NR₈CR₉(C═O)NR₈R₉;    -   (g) C₄₋₁₀ heterocyclyl which is optionally substituted on either        the carbon or the heteroatom with one to three substituents        selected from C₁₋₆ alkyl, halo, OR₄, NR₈R₄, —(CO)R₈, (CO)—NR₈R₉        or phenyl (which is optionally substituted with C₁₋₆ alkyl, OR₄,        NR₈R₄, heterocyclyl, —(CO)R₈ or —(CO)—NR₈R₉);-   R₆ is    -   (a) hydrogen;    -   (b) C₁₋₈ alkyl, which is optionally substituted with halo,        hydroxyl, amino, aryl, cycloalkyl or heterocyclyl;    -   (c) C₃₋₁₀ cycloalkyl, which is optionally substituted with C₁₋₆        alkyl, (C₁₋₆ alkyl)aryl, (C₁₋₆ alkyl)OR₉, OR₄, NR₈R₄, phenyl        (which is optionally substituted with C₁₋₆ alkyl, OR₄, NR₈R₄,        heterocyclyl, —(CO)R₈ or —(CO)—NR₈R₉;    -   (d) —(CO)R₈;    -   (e) —(CO)—NR₈R₉;    -   (f) C₁₋₆ alkyl(C═O)NR₈CR₉(C═O)NR₈R₉;    -   (g) C₄₋₁₀ heterocyclyl which is optionally substituted on either        the carbon or the heteroatom with one to three substituents        selected from C₁₋₆ alkyl, halo, OR₄, NR₈R₄, —(CO)R₈, (CO)—NR₈R₉        or phenyl (which is optionally substituted with C₁₋₆ alkyl, OR₄,        NR₈R₄, heterocyclyl, —(CO)R₈ or —(CO)—NR₈R₉);-   R₇ is    -   (a) hydrogen;    -   (b) C₁₋₆ alkyl, which is optionally substituted with halo,        hydroxyl, amino, phenyl or heterocyclyl;    -   (c) C₃₋₁₀ cycloalkyl, which is optionally substituted with C₁₋₆        alkyl, OR₄, NR₈R₄, phenyl (which is optionally substituted with        C₁₋₆ alkyl, OR₄, NR₈R₄, heterocyclyl, —(CO)R₈ or —(CO)—NR₈R₉);    -   (d) C₄₋₁₀ heterocyclyl which is optionally substituted on either        the carbon or the heteroatom with C₁₋₆ alkyl, OR₄, NR₈R₄, phenyl        (which is optionally substituted with C₁₋₆ alkyl, OR₄, NR₈R₄,        heterocyclyl, —(CO)R₈ or —(CO)—NR₈R₉);        Or R₅ and R₆, together with the atoms between them, can form a        three to ten membered heterocyclic or heteroaryl ring which is        optionally substituted with C₁₋₆ alkyl, (C₁₋₆ alkyl)aryl, (C₁₋₆        alkenyl)aryl, (C₁₋₆ alkyl)OR₉, OR₄, NR₈R₄, phenyl (which is        optionally substituted with C₁₋₆ alkyl, OR₄, NR₈R₄,        heterocyclyl, —(CO)R₈ or —(CO)—NR₈R₉), —(CO)R₈; —(CO)—NR8R9, or        heterocyclyl;-   R₈ is hydrogen or C₁₋₆ alkyl, —(CO)R₁₁, —(CO)N(R₁₁)₁₂;-   R₉ is hydrogen or C₁₋₆ alkyl;-   R₁₀ is:    -   (a) hydrogen;    -   (b) CO₂R₁₁;    -   (c) C(O)R₁₁;    -   (d) NHR₁;    -   (e) NR₁₁R₁₂;    -   (f) NHS(O)₂R₁₁;    -   (g) NHC(O)R₁₁;    -   (h) NHC(O)OR₁₁;    -   (i) NH—C═(NH)NH₂;    -   (j) NHC(O)NH₂;    -   (k) NHC(O)NHR₁₁;    -   (l) NHC(O)NR₁₁R₁₂;    -   (m) NC3-6cycloalkyl;    -   (n) C(O)NHR₁₁;    -   (o) C(O)NR₁₁R₁₂;    -   (p) SO₂NHR₁₁;    -   (q) SO₂NHC(O)R₁₂; or    -   (r) SO₂R₁₁;-   R₁₁ is selected from the group consisting of:    -   (a) hydrogen,    -   (b) C₃₋₆cycloalkyl, which is optionally substituted with aryl,        heteroaryl or one to five halo;    -   (c) C₁₋₆ alkyl, which is optionally substituted with aryl,        heteroaryl, or one to five halo;    -   (d) Aryl, which is optionally substituted with one to five halo;    -   (e) Heteroaryl (wherein the heteroaryl has 5 or 6 members in        which 1, 2, 3, or 4 of the atoms is a heteroatom selected from        N, S and O), which is optionally substituted with one to five        halo;-   R₁₂ is selected from the group consisting of:    -   (a) hydrogen,    -   (b) C₁₋₆alkyl, which is optionally substituted with aryl,        heteroaryl or one to five halo;    -   (c) C₃₋₆cycloalkyl, which is optionally substituted with aryl,        heteroaryl or one to five halo;    -   (d) Aryl, which is optionally substituted with one to five halo;    -   (e) Heteroaryl (wherein the heteroaryl has 5 or 6 members in        which 1, 2, 3, or 4 of the atoms is a heteroatom selected from        N, S and O), which is optionally substituted with one to five        halo;        A is absent or is selected from the group consisting of: aryl or        heteroaryl (wherein the heteroaryl is a monocyclic ring of 5 or        6 atoms or a bicyclic ring of 9 or 10 atoms in which 1, 2, 3, or        4 of the atoms is a heteroatom selected from N, S and O),        wherein said aryl or heteroaryl is optionally substituted with        one or more substituents selected from halo, (C₁₋₃)alkyl,        —C(O)OH, CF₃, —SO₂(C₁₋₃)alkyl, SO₂N(C₁₋₃)alkyl,        SO₂NHC(O)—(C₁₋₃)alkyl or N(CH₃)₂;        L is absent or is selected from the group consisting of:        —(CH₂)k-W-, —Z—(CH₂)k-, —C≡C—, —C₁₋₆alkyl-, —C₃₋₆cycloalkyl- and        —C₂₋₅alkene-, wherein the alkene is optionally substituted with        one or more groups selected from C₁₋₆alkyl or C₁₋₆cycloalkyl;        W is selected from the group consisting of: O, NH, NC₁₋₆alkyl        and S(O)m, with the proviso that when W is O, S(O)m, NH or        NC₁₋₆alkyl and simultaneously A is absent then R₁₀ is CO₂R₁₁,        COR₁₁, CONHR₁₁ or CONR₁₁R₁₂;        k=0, 1, 2, 3, 4, or 5;        m=0, 1, or 2; and        n=0, 1, 2, or 3.

In a preferred embodiment, the JAK-2 inhibitor is((R)-7-(2-aminopyrimidin-5-yl)-1-((1-cyclopropyl-2,2,2-trifluoroethyl)amino)-5H-pyrido[4,3-b]indole-4-carboxamide,which is also named7-(2-aminopyrimidin-5-yl)-1-{[(1R)-1-cyclopropyl-2,2,2-trifluoroethyl]amino}-5H-pyrido[4,3-b]indole-4-carboxamide.In a preferred embodiment, the JAK-2 inhibitor is a compound of Formula(LXII):

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. The preparation of this compound is known to those ofordinary skill in the art, and is described in Lim, et al., Discovery of1-amino-5H-pyrido[4,3-b]indol-4-carboxamide inhibitors of Janus kinase-2(JAK2) for the treatment of myeloproliferative disorders, J. Med. Chem.2011, 54, 7334-7349, the disclosure of which is incorporated byreference herein.

In an embodiment, the JAK-2 inhibitor is a compound selected from theJAK-2 inhibitors disclosed in U.S. Patent No. U.S. Pat. No. 8,518,964 orU.S. Patent Application Publication Nos. 2010/0048551 A1, thedisclosures of which are incorporated by reference herein.

Pharmaceutical Compositions

In one embodiment, the invention provides a pharmaceutical compositionfor use in the treatment of the diseases and conditions describedherein. In a preferred embodiment, the invention provides pharmaceuticalcompositions, including those described below, for use in the treatmentof a hyperproliferative disease. In a preferred embodiment, theinvention provides pharmaceutical compositions, including thosedescribed below, for use in the treatment of cancer.

In some embodiments, the invention provides pharmaceutical compositionsfor treating solid tumor cancers, lymphomas and leukemia.

In preferred embodiments, the invention provides a compositioncomprising therapeutically effective amounts of (1) a JAK-2 inhibitor ora pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; and (2) a BTK inhibitor or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, foruse in the treatment of cancer. This composition is typically apharmaceutical composition.

In preferred embodiments, the invention provides a compositioncomprising therapeutically effective amounts of (1) a JAK-2 inhibitor ora pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; (2) a BTK inhibitor or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof; and (3) a PI3Kinhibitor or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof. This composition is typically apharmaceutical composition.

In preferred embodiments, the invention provides a compositioncomprising therapeutically effective amounts of (1) a JAK-2 inhibitor ora pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; (2) a BTK inhibitor or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof; and (3) a PI3K-δinhibitor or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof. This composition is typically apharmaceutical composition.

In preferred embodiments, the invention provides a compositioncomprising therapeutically effective amounts of (1) a JAK-2 inhibitor ora pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; (2) a BTK inhibitor or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof; and (3) ananti-CD20 antibody selected from the group consisting of rituximab,obinutuzumab, ofatumumab, veltuzumab, tositumomab, ibritumomab, andfragments, derivatives, conjugates, variants, radioisotope-labeledcomplexes, and biosimilars thereof. This composition is typically apharmaceutical composition.

In preferred embodiments, the invention provides a compositioncomprising therapeutically effective amounts of (1) a JAK-2 inhibitor ora pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; (2) a BTK inhibitor or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof; (3) a PI3Kinhibitor or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof; and (4) an anti-CD20 antibody selectedfrom the group consisting of rituximab, obinutuzumab, ofatumumab,veltuzumab, tositumomab, ibritumomab, and fragments, derivatives,conjugates, variants, radioisotope-labeled complexes, and biosimilarsthereof. This composition is typically a pharmaceutical composition.

In some embodiments, the invention provides a composition comprisingtherapeutically effective amounts of (1) a JAK-2 inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; (2) a BTK inhibitor or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof; (3) a PI3K-δinhibitor or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof; and (4) an anti-CD20 antibody selectedfrom the group consisting of rituximab, obinutuzumab, ofatumumab,veltuzumab, tositumomab, ibritumomab, and fragments, derivatives,conjugates, variants, radioisotope-labeled complexes, and biosimilarsthereof. This composition is typically a pharmaceutical composition.

In some embodiments, the invention provides a composition comprisingtherapeutically effective amounts of (1) a JAK-2 inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; (2) a BTK inhibitor or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof; and (3) acompound selected from the group consisting of gemcitabine,albumin-bound paclitaxel, bendamustine, fludarabine, cyclophosphamide,chlorambucil, an anticoagulant or antiplatelet active pharmaceuticalingredient, or combinations thereof. This composition is typically apharmaceutical composition.

In some embodiments, the invention provides a composition comprisingtherapeutically effective amounts of (1) a JAK-2 inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; (2) a BTK inhibitor or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof; (3) a PI3Kinhibitor or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof; and (4) a compound selected from thegroup consisting of gemcitabine, albumin-bound paclitaxel, bendamustine,fludarabine, cyclophosphamide, chlorambucil, an anticoagulant orantiplatelet active pharmaceutical ingredient, and combinations thereof.This composition is typically a pharmaceutical composition.

In some embodiments, the invention provides a composition comprisingtherapeutically effective amounts of (1) a JAK-2 inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; (2) a BTK inhibitor or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof; (3) a PI3K-δinhibitor or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof; and (4) a compound selected from thegroup consisting of gemcitabine, albumin-bound paclitaxel, bendamustine,fludarabine, cyclophosphamide, chlorambucil, an anticoagulant orantiplatelet active pharmaceutical ingredient, and combinations thereof.This composition is typically a pharmaceutical composition.

In some embodiments, the invention provides a composition comprisingtherapeutically effective amounts of (1) a JAK-2 inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; (2) a BTK inhibitor or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof, for use in thetreatment of cancer; (3) an anti-CD20 antibody selected from the groupconsisting of rituximab, obinutuzumab, ofatumumab, veltuzumab,tositumomab, ibritumomab, and fragments, derivatives, conjugates,variants, radioisotope-labeled complexes, biosimilars thereof, andcombinations thereof; and (4) a compound selected from the groupconsisting of gemcitabine, albumin-bound paclitaxel, bendamustine,fludarabine, cyclophosphamide, chlorambucil, an anticoagulant orantiplatelet active pharmaceutical ingredient, and combinations thereof.This composition is typically a pharmaceutical composition.

In some embodiments, the invention provides a composition comprisingtherapeutically effective amounts of (1) a JAK-2 inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; (2) a BTK inhibitor or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof; (3) a PI3Kinhibitor or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof; (4) an anti-CD20 antibody selected fromthe group consisting of rituximab, obinutuzumab, ofatumumab, veltuzumab,tositumomab, ibritumomab, and fragments, derivatives, conjugates,variants, radioisotope-labeled complexes, biosimilars thereof, andcombinations thereof; and (5) a compound selected from the groupconsisting of gemcitabine, albumin-bound paclitaxel, bendamustine,fludarabine, cyclophosphamide, chlorambucil, an anticoagulant orantiplatelet active pharmaceutical ingredient, and combinations thereof.This composition is typically a pharmaceutical composition.

In some embodiments, the invention provides a composition comprisingtherapeutically effective amounts of (1) a JAK-2 inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; (2) a BTK inhibitor or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof; (3) a PI3K-δinhibitor or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof; (4) an anti-CD20 antibody selected fromthe group consisting of rituximab, obinutuzumab, ofatumumab, veltuzumab,tositumomab, ibritumomab, and fragments, derivatives, conjugates,variants, radioisotope-labeled complexes, and biosimilars thereof; and(5) a compound selected from the group consisting of gemcitabine,albumin-bound paclitaxel, bendamustine, fludarabine, cyclophosphamide,chlorambucil, an anticoagulant or antiplatelet active pharmaceuticalingredient, and combinations thereof. This composition is typically apharmaceutical composition.

In some embodiments, the invention provides a composition comprisingtherapeutically effective amounts of (1) a JAK-2 inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; and (2) a BTK inhibitor having the structure:

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. This composition is typically a pharmaceuticalcomposition.

In some embodiments, the invention provides a composition comprisingtherapeutically effective amounts of (1) a JAK-2 inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, (2) a BTK inhibitor having the structure:

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; and (3) a PI3K inhibitor or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. Thiscomposition is typically a pharmaceutical composition.

In some embodiments, the invention provides a composition comprisingtherapeutically effective amounts of (1) a JAK-2 inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; (2) a BTK inhibitor having the structure:

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; and (3) a PI3K-δ inhibitor or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. Thiscomposition is typically a pharmaceutical composition.

In some embodiments, the invention provides a composition comprisingtherapeutically effective amounts of (1) a JAK-2 inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; (2) a BTK inhibitor having the structure:

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; and (3) an anti-CD20 antibody selected from the groupconsisting of rituximab, obinutuzumab, ofatumumab, veltuzumab,tositumomab, ibritumomab, and fragments, derivatives, conjugates,variants, radioisotope-labeled complexes, and biosimilars thereof. Thiscomposition is typically a pharmaceutical composition.

In some embodiments, the invention provides a composition comprisingtherapeutically effective amounts of (1) a JAK-2 inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; (2) a BTK inhibitor having the structure:

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; (3) a PI3K inhibitor or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof; and (4) ananti-CD20 antibody selected from the group consisting of rituximab,obinutuzumab, ofatumumab, veltuzumab, tositumomab, ibritumomab, andfragments, derivatives, conjugates, variants, radioisotope-labeledcomplexes, and biosimilars thereof. This composition is typically apharmaceutical composition.

In some embodiments, the invention provides a composition comprisingtherapeutically effective amounts of (1) a JAK-2 inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; (2) a BTK inhibitor having the structure:

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; (3) a PI3K-δ inhibitor or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof; and (4) ananti-CD20 antibody selected from the group consisting of rituximab,obinutuzumab, ofatumumab, veltuzumab, tositumomab, ibritumomab, andfragments, derivatives, conjugates, variants, radioisotope-labeledcomplexes, and biosimilars thereof. This composition is typically apharmaceutical composition.

In some embodiments, the invention provides a composition comprisingtherapeutically effective amounts of (1) a JAK-2 inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; and (2) a BTK inhibitor selected from the groupconsisting of:

and pharmaceutically-acceptable salts, cocrystals, hydrates, solvates,and prodrugs thereof. This composition is typically a pharmaceuticalcomposition.

In some embodiments, the invention provides a composition comprisingtherapeutically effective amounts of (1) a JAK-2 inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; (2) a BTK inhibitor selected from the group consistingof:

and pharmaceutically-acceptable salts, cocrystals, hydrates, solvates,and prodrugs thereof; and (3) a PI3K inhibitor or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. Thiscomposition is typically a pharmaceutical composition.

In some embodiments, the invention provides a composition comprisingtherapeutically effective amounts of (1) a JAK-2 inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; (2) a BTK inhibitor selected from the group consistingof:

and pharmaceutically-acceptable salts, cocrystals, hydrates, solvates,and prodrugs thereof; and (3) a PI3K-δ inhibitor or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. Thiscomposition is typically a pharmaceutical composition.

In some embodiments, the invention provides a composition comprisingtherapeutically effective amounts of (1) a JAK-2 inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; (2) a BTK inhibitor selected from the group consistingof:

and pharmaceutically-acceptable salts, cocrystals, hydrates, solvates,and prodrugs thereof, and (3) an anti-CD20 antibody selected from thegroup consisting of rituximab, obinutuzumab, ofatumumab, veltuzumab,tositumomab, ibritumomab, and fragments, derivatives, conjugates,variants, radioisotope-labeled complexes, and biosimilars thereof. Thiscomposition is typically a pharmaceutical composition.

In some embodiments, the invention provides a composition comprisingtherapeutically effective amounts of (1) a JAK-2 inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; (2) a BTK inhibitor selected from the group consistingof:

and pharmaceutically-acceptable salts, cocrystals, hydrates, solvates,and prodrugs thereof; (3) a PI3K inhibitor or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof; and(4) an anti-CD20 antibody selected from the group consisting ofrituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab,ibritumomab, and fragments, derivatives, conjugates, variants,radioisotope-labeled complexes, and biosimilars thereof. Thiscomposition is typically a pharmaceutical composition.

In some embodiments, the invention provides a composition comprisingtherapeutically effective amounts of (1) a JAK-2 inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; (2) a BTK inhibitor selected from the group consistingof:

and pharmaceutically-acceptable salts, cocrystals, hydrates, solvates,and prodrugs thereof, (3) a PI3K-δ inhibitor or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof; and(4) an anti-CD20 antibody selected from the group consisting ofrituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab,ibritumomab, and fragments, derivatives, conjugates, variants,radioisotope-labeled complexes, and biosimilars thereof. Thiscomposition is typically a pharmaceutical composition.

In some embodiments, the invention provides a composition comprisingtherapeutically effective amounts of (1) a JAK-2 inhibitor selected fromthe group consisting of ruxolitinib, pacritinib, andpharmaceutically-acceptable salts, cocrystals, hydrates, solvates, andprodrugs thereof; and (2) a BTK inhibitor or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. Thiscomposition is typically a pharmaceutical composition.

In some embodiments, the invention provides a composition comprisingtherapeutically effective amounts of (1) a JAK-2 inhibitor selected fromthe group consisting of:

and pharmaceutically-acceptable salts, cocrystals, hydrates, solvates,and prodrugs thereof; and (2) a BTK inhibitor or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. Thiscomposition is typically a pharmaceutical composition.

In some embodiments, the invention provides a composition comprisingtherapeutically effective amounts of (1) a JAK-2 inhibitor selected fromthe group consisting of ruxolitinib, pacritinib, andpharmaceutically-acceptable salts, cocrystals, hydrates, solvates, andprodrugs thereof; (2) a BTK inhibitor or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof; and (3) a PI3K-δinhibitor or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof. This composition is typically apharmaceutical composition.

In some embodiments, the invention provides a composition comprisingtherapeutically effective amounts of (1) a JAK-2 inhibitor selected fromthe group consisting of:

and pharmaceutically-acceptable salts, cocrystals, hydrates, solvates,and prodrugs thereof; (2) a BTK inhibitor or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof; and(3) a PI3K-δ inhibitor or a pharmaceutically acceptable salt, solvate,hydrate, cocrystal, or prodrug thereof. This composition is typically apharmaceutical composition.

In some embodiments, the invention provides a composition comprisingtherapeutically effective amounts of (1) a JAK-2 inhibitor selected fromthe group consisting of ruxolitinib, pacritinib, andpharmaceutically-acceptable salts, cocrystals, hydrates, solvates, andprodrugs thereof; (2) a BTK inhibitor or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof, for use in thetreatment of cancer; and (3) an anti-CD20 antibody selected from thegroup consisting of rituximab, obinutuzumab, ofatumumab, veltuzumab,tositumomab, ibritumomab, and fragments, derivatives, conjugates,variants, radioisotope-labeled complexes, and biosimilars thereof. Thiscomposition is typically a pharmaceutical composition.

In some embodiments, the invention provides a composition comprisingtherapeutically effective amounts of (1) a JAK-2 inhibitor selected fromthe group consisting of ruxolitinib, pacritinib, andpharmaceutically-acceptable salts, cocrystals, hydrates, solvates, andprodrugs thereof; (2) a BTK inhibitor or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof; (3) a PI3Kinhibitor or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof; and (4) an anti-CD20 antibody selectedfrom the group consisting of rituximab, obinutuzumab, ofatumumab,veltuzumab, tositumomab, ibritumomab, and fragments, derivatives,conjugates, variants, radioisotope-labeled complexes, and biosimilarsthereof. This composition is typically a pharmaceutical composition.

In some embodiments, the invention provides a composition comprisingtherapeutically effective amounts of (1) a JAK-2 inhibitor selected fromthe group consisting of ruxolitinib, pacritinib, andpharmaceutically-acceptable salts, cocrystals, hydrates, solvates, orprodrugs thereof; (2) a BTK inhibitor or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof; (3) a PI3K-δinhibitor or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof; and (4) a therapeutically effectiveamount of an anti-CD20 antibody selected from the group consisting ofrituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab,ibritumomab, and fragments, derivatives, conjugates, variants,radioisotope-labeled complexes, and biosimilars thereof. Thiscomposition is typically a pharmaceutical composition.

In some embodiments, the invention provides a composition comprisingtherapeutically effective amounts of (1) a JAK-2 inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; (2) a BTK inhibitor or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof; and (3) a PI3Kinhibitor selected from the group consisting of:

and pharmaceutically acceptable salts, solvates, hydrates, cocrystals,and prodrugs thereof. This composition is typically a pharmaceuticalcomposition.

In some embodiments, the invention provides a composition comprisingtherapeutically effective amounts of (1) a JAK-2 inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; (2) a BTK inhibitor or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof; and (3) a PI3K-δinhibitor selected from the group consisting of:

and pharmaceutically acceptable salts, solvates, hydrates, cocrystals,and prodrugs thereof. This composition is typically a pharmaceuticalcomposition.

In one embodiment, the invention provides a composition comprisingtherapeutically effective amounts of (1) a JAK-2 inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; (2) a BTK inhibitor or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof; and (3) a PI3K-δinhibitor selected from the group consisting of:

and pharmaceutically acceptable salts, solvates, hydrates, cocrystals,and prodrugs thereof; and (4) a therapeutically effective amount of ananti-CD20 antibody selected from the group consisting of rituximab,obinutuzumab, ofatumumab, veltuzumab, tositumomab, ibritumomab, andfragments, derivatives, conjugates, variants, radioisotope-labeledcomplexes, and biosimilars thereof. This composition is typically apharmaceutical composition.

The pharmaceutical compositions are typically formulated to provide atherapeutically effective amount of a combination as described herein,i.e., a combination of a PI3K inhibitor, including a PI3K-γ or PI3K-δinhibitor, a JAK-2 inhibitor, and/or a BTK inhibitor as the activeingredients, or pharmaceutically acceptable salts, prodrugs, solvates,or hydrates thereof. Where desired, the pharmaceutical compositionscontain a pharmaceutically acceptable salt and/or coordination complexof one or more of the active ingredients. Typically, the pharmaceuticalcompositions also comprise one or more pharmaceutically acceptableexcipients, carriers, including inert solid diluents and fillers,diluents, including sterile aqueous solution and various organicsolvents, permeation enhancers, solubilizers and adjuvants.

The pharmaceutical compositions described above are preferably for usein the treatment of the diseases and conditions described below. In apreferred embodiment, the pharmaceutical compositions are for use in thetreatment of cancer. In preferred embodiments, the pharmaceuticalcompositions are for use in treating solid tumor cancers, lymphomas, andleukemias.

In a preferred embodiment, the pharmaceutical compositions of thepresent invention are for use in the treatment of cancer. In oneembodiment, the pharmaceutical compositions of the present invention arefor use in the treatment of a cancer selected from the group consistingof bladder cancer, squamous cell carcinoma including head and neckcancer, pancreatic ductal adenocarcinoma (PDA), pancreatic cancer, coloncarcinoma, mammary carcinoma, breast cancer, fibrosarcoma, mesothelioma,renal cell carcinoma, lung carcinoma, thyoma, prostate cancer,colorectal cancer, ovarian cancer, acute myeloid leukemia, thymuscancer, brain cancer, squamous cell cancer, skin cancer, eye cancer,retinoblastoma, melanoma, intraocular melanoma, oral cavity andoropharyngeal cancers, gastric cancer, stomach cancer, cervical cancer,renal cancer, kidney cancer, liver cancer, ovarian cancer, esophagealcancer, testicular cancer, gynecological cancer, thyroid cancer, aquiredimmune deficiency syndrome (AIDS)-related cancers (e.g., lymphoma andKaposi's sarcoma), viral-induced cancer, glioblastoma, esophogealtumors, hematological neoplasms, non-small-cell lung cancer, chronicmyelocytic leukemia, diffuse large B-cell lymphoma, esophagus tumor,follicle center lymphoma, head and neck tumor, hepatitis C virusinfection, hepatocellular carcinoma, Hodgkin's disease, metastatic coloncancer, multiple myeloma, non-Hodgkin's lymphoma, indolent non-Hodgkin'slymphoma, ovary tumor, pancreas tumor, renal cell carcinoma, small-celllung cancer, stage IV melanoma, chronic lymphocytic leukemia, B-cellacute lymphoblastic leukemia (ALL), mature B-cell ALL, follicularlymphoma, mantle cell lymphoma, and Burkitt's lymphoma.

The pharmaceutical compositions are administered as a combination of aJAK-2 inhibitor with a PI3K inhibitor, which may be a PI3K-γ or PI3K-δinhibitor, and/or a BTK inhibitor. Where desired, other activepharmaceutical ingredient(s) may be mixed into a preparation or two ormore components of the combination may be formulated into separatepreparations for use in combination separately or at the same time. Akit containing the components of the combination, formulated intoseparate preparations for said use, in also provided by the invention.

In an embodiment, the molar ratio of the JAK-2 inhibitor to the BTKinhibitor in the pharmaceutical compositions is in the range from 10:1to 1:10, preferably from 2.5:1 to 1:2.5, and more preferably about 1:1.In an embodiment, the molar ratio of the JAK-2 inhibitor to the PI3Kinhibitor in the pharmaceutical compositions is in the range from 10:1to 1:10, preferably from 2.5:1 to 1:2.5, and more preferably about 1:1.In an embodiment, the weight ratio of the JAK-2 inhibitor to the BTKinhibitor in the pharmaceutical compositions is selected from the groupconsisting of 20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1,11:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4,1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17,1:18, 1:19, and 1:20. In an embodiment, the weight ratio of the JAK-2inhibitor to the PI3K inhibitor in the pharmaceutical compositions isselected from the group consisting of 20:1, 19:1, 18:1, 17:1, 16:1,15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1,2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12,1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, and 1:20.

In some embodiments, the concentration of each of the PI3K, JAK-2, andBTK inhibitors provided in the pharmaceutical compositions of theinvention is less than, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%,30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%,6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%,0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%,0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%,0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w/w, w/vor v/v of the pharmaceutical composition.

In some embodiments, the concentration of each of the PI3K, JAK-2, andBTK inhibitors provided in the pharmaceutical compositions of theinvention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%,19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%,17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%,14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%,12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%,9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%,6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%,3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%,1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%,0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%,0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%,0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w/w, w/v, or v/v of thepharmaceutical composition.

In some embodiments, the concentration of each of the PI3K, JAK-2 andBTK inhibitors provided in the pharmaceutical compositions is in therange from about 0.0001% to about 50%, about 0.001% to about 40%, about0.01% to about 30%, about 0.02% to about 29%, about 0.03% to about 28%,about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about25%, about 0.07% to about 24%, about 0.08% to about 23%, about 0.09% toabout 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3%to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%,about 0.9% to about 12% or about 1% to about 10% w/w, w/v or v/v of thepharmaceutical composition.

In some embodiments, the concentration of each of the PI3K, JAK-2, andBTK inhibitors provided in the pharmaceutical compositions is in therange from about 0.001% to about 10%, about 0.01% to about 5%, about0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%,about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about2%, about 0.08% to about 1.5%, about 0.09% to about 1%, about 0.1% toabout 0.9% w/w, w/v or v/v of the pharmaceutical composition.

In some embodiments, the amount of each of the PI3K, JAK-2, and BTKinhibitors provided in the pharmaceutical compositions is equal to orless than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g,5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g,0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g,0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g,0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g,0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g,0.0002 g, or 0.0001 g.

In some embodiments, the amount of each of the PI3K, JAK-2, and BTKinhibitors provided in the pharmaceutical compositions is more than0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g,0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g,0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g,0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, 0.15g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5 g, 0.55 g, 0.6 g,0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g,2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g, 7.5 g, 8 g, 8.5g, 9 g, 9.5 g, or 10 g.

Each of the PI3K, JAK-2, and BTK inhibitors according to the inventionis effective over a wide dosage range. For example, in the treatment ofadult humans, dosages independently range from 0.01 to 1000 mg, from 0.5to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day areexamples of dosages that may be used. The exact dosage will depend uponthe route of administration, the form in which the compound isadministered, the gender and age of the subject to be treated, the bodyweight of the subject to be treated, and the preference and experienceof the attending physician.

In a preferred embodiment, the pharmaceutical compositions of thepresent invention are for use in the treatment of cancer. In a preferredembodiment, the pharmaceutical compositions of the present invention arefor use in the treatment of a cancer selected from the group consistingof bladder cancer, squamous cell carcinoma including head and neckcancer, pancreatic ductal adenocarcinoma (PDA), pancreatic cancer, coloncarcinoma, mammary carcinoma, breast cancer, fibrosarcoma, mesothelioma,renal cell carcinoma, lung carcinoma, thyoma, prostate cancer,colorectal cancer, ovarian cancer, acute myeloid leukemia, thymuscancer, brain cancer, squamous cell cancer, skin cancer, eye cancer,retinoblastoma, melanoma, intraocular melanoma, oral cavity andoropharyngeal cancers, gastric cancer, stomach cancer, cervical cancer,renal cancer, kidney cancer, liver cancer, ovarian cancer, esophagealcancer, testicular cancer, gynecological cancer, thyroid cancer, aquiredimmune deficiency syndrome (AIDS)-related cancers (e.g., lymphoma andKaposi's sarcoma), viral-induced cancer, glioblastoma, esophogealtumors, hematological neoplasms, non-small-cell lung cancer, chronicmyelocytic leukemia, diffuse large B-cell lymphoma, esophagus tumor,follicle center lymphoma, head and neck tumor, hepatitis C virusinfection, hepatocellular carcinoma, Hodgkin's disease, metastatic coloncancer, multiple myeloma, non-Hodgkin's lymphoma, indolent non-Hodgkin'slymphoma, ovary tumor, pancreas tumor, renal cell carcinoma, small-celllung cancer, stage IV melanoma, chronic lymphocytic leukemia, B-cellacute lymphoblastic leukemia (ALL), mature B-cell ALL, follicularlymphoma, mantle cell lymphoma, and Burkitt's lymphoma.

Described below are non-limiting pharmaceutical compositions and methodsfor preparing the same.

Pharmaceutical Compositions for Oral Administration

In preferred embodiments, the invention provides a pharmaceuticalcomposition for oral administration containing the combination of aPI3K, JAK-2, and BTK inhibitor, and a pharmaceutical excipient suitablefor oral administration.

In preferred embodiments, the invention provides a solid pharmaceuticalcomposition for oral administration containing: (i) an effective amountof each of a PI3K, JAK-2, and BTK inhibitor in combination and (ii) apharmaceutical excipient suitable for oral administration. In someembodiments, the composition further contains (iii) an effective amountof a fourth active pharmaceutical ingredient.

In some embodiments, the invention provides a solid pharmaceuticalcomposition for oral administration containing: (i) an effective amountof a JAK-2 inhibitor in combination with a PI3K inhibitor and (ii) apharmaceutical excipient suitable for oral administration. In selectedembodiments, the composition further contains (iii) an effective amountof a third active pharmaceutical ingredient.

In preferred embodiments, the invention provides a solid pharmaceuticalcomposition for oral administration containing: (i) an effective amountof a JAK-2 inhibitor in combination with a BTK inhibitor and (ii) apharmaceutical excipient suitable for oral administration. In selectedembodiments, the composition further contains (iii) an effective amountof a third active pharmaceutical ingredient.

In some embodiments, the pharmaceutical composition may be a liquidpharmaceutical composition suitable for oral consumption. Pharmaceuticalcompositions of the invention suitable for oral administration can bepresented as discrete dosage forms, such as capsules, cachets, ortablets, or liquids or aerosol sprays each containing a predeterminedamount of an active ingredient as a powder or in granules, a solution,or a suspension in an aqueous or nonaqueous liquid, an oil-in-wateremulsion, or a water-in-oil liquid emulsion. Such dosage forms can beprepared by any of the methods of pharmacy, but all methods include thestep of bringing the active ingredient(s) into association with thecarrier, which constitutes one or more necessary ingredients. Ingeneral, the compositions are prepared by uniformly and intimatelyadmixing the active ingredient(s) with liquid carriers or finely dividedsolid carriers or both, and then, if necessary, shaping the product intothe desired presentation. For example, a tablet can be prepared bycompression or molding, optionally with one or more accessoryingredients. Compressed tablets can be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such aspowder or granules, optionally mixed with an excipient such as, but notlimited to, a binder, a lubricant, an inert diluent, and/or a surfaceactive or dispersing agent. Molded tablets can be made by molding in asuitable machine a mixture of the powdered compound moistened with aninert liquid diluent.

The invention further encompasses anhydrous pharmaceutical compositionsand dosage forms since water can facilitate the degradation of somecompounds. For example, water may be added (e.g., 5%) in thepharmaceutical arts as a means of simulating long-term storage in orderto determine characteristics such as shelf-life or the stability offormulations over time. Anhydrous pharmaceutical compositions and dosageforms of the invention can be prepared using anhydrous or low moisturecontaining ingredients and low moisture or low humidity conditions.Pharmaceutical compositions and dosage forms of the invention whichcontain lactose can be made anhydrous if substantial contact withmoisture and/or humidity during manufacturing, packaging, and/or storageis expected. An anhydrous pharmaceutical composition may be prepared andstored such that its anhydrous nature is maintained. Accordingly,anhydrous compositions may be packaged using materials known to preventexposure to water such that they can be included in suitable formularykits. Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastic or the like, unit dose containers,blister packs, and strip packs.

Each of the PI3K, JAK-2, and BTK inhibitors as active ingredients can becombined in an intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier can take a wide variety of forms depending on the form ofpreparation desired for administration. In preparing the compositionsfor an oral dosage form, any of the usual pharmaceutical media can beemployed as carriers, such as, for example, water, glycols, oils,alcohols, flavoring agents, preservatives, coloring agents, and the likein the case of oral liquid preparations (such as suspensions, solutions,and elixirs) or aerosols; or carriers such as starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents can be used in the case of oral solidpreparations, in some embodiments without employing the use of lactose.For example, suitable carriers include powders, capsules, and tablets,with the solid oral preparations. If desired, tablets can be coated bystandard aqueous or nonaqueous techniques.

Binders suitable for use in pharmaceutical compositions and dosage formsinclude, but are not limited to, corn starch, potato starch, or otherstarches, gelatin, natural and synthetic gums such as acacia, sodiumalginate, alginic acid, other alginates, powdered tragacanth, guar gum,cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate,carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch,hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixturesthereof.

Examples of suitable fillers for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

Disintegrants may be used in the compositions of the invention toprovide tablets that disintegrate when exposed to an aqueousenvironment. Too much of a disintegrant may produce tablets whichdisintegrate in the bottle. Too little may be insufficient fordisintegration to occur, thus altering the rate and extent of release ofthe active ingredients from the dosage form. Thus, a sufficient amountof disintegrant that is neither too little nor too much to detrimentallyalter the release of the active ingredient(s) may be used to form thedosage forms of the compounds disclosed herein. The amount ofdisintegrant used may vary based upon the type of formulation and modeof administration, and may be readily discernible to those of ordinaryskill in the art. About 0.5 to about 15 weight percent of disintegrant,or about 1 to about 5 weight percent of disintegrant, may be used in thepharmaceutical composition. Disintegrants that can be used to formpharmaceutical compositions and dosage forms of the invention include,but are not limited to, agar-agar, alginic acid, calcium carbonate,microcrystalline cellulose, croscarmellose sodium, crospovidone,polacrilin potassium, sodium starch glycolate, potato or tapioca starch,other starches, pre-gelatinized starch, other starches, clays, otheralgins, other celluloses, gums or mixtures thereof.

Lubricants which can be used to form pharmaceutical compositions anddosage forms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethylaureate, agar, ormixtures thereof. Additional lubricants include, for example, a syloidsilica gel, a coagulated aerosol of synthetic silica, or mixturesthereof. A lubricant can optionally be added, in an amount of less thanabout 1 weight percent of the pharmaceutical composition.

When aqueous suspensions and/or elixirs are desired for oraladministration, the essential active ingredient therein may be combinedwith various sweetening or flavoring agents, coloring matter or dyesand, if so desired, emulsifying and/or suspending agents, together withsuch diluents as water, ethanol, propylene glycol, glycerin and variouscombinations thereof.

The tablets can be uncoated or coated by known techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearate canbe employed. Formulations for oral use can also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin, or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example, peanut oil, liquidparaffin or olive oil.

Surfactants which can be used to form pharmaceutical compositions anddosage forms of the invention include, but are not limited to,hydrophilic surfactants, lipophilic surfactants, and mixtures thereof.That is, a mixture of hydrophilic surfactants may be employed, a mixtureof lipophilic surfactants may be employed, or a mixture of at least onehydrophilic surfactant and at least one lipophilic surfactant may beemployed.

A suitable hydrophilic surfactant may generally have an HLB value of atleast 10, while suitable lipophilic surfactants may generally have anHLB value of or less than about 10. An empirical parameter used tocharacterize the relative hydrophilicity and hydrophobicity of non-ionicamphiphilic compounds is the hydrophilic-lipophilic balance (“HLB”value). Surfactants with lower HLB values are more lipophilic orhydrophobic, and have greater solubility in oils, while surfactants withhigher HLB values are more hydrophilic, and have greater solubility inaqueous solutions. Hydrophilic surfactants are generally considered tobe those compounds having an HLB value greater than about 10, as well asanionic, cationic, or zwitterionic compounds for which the HLB scale isnot generally applicable. Similarly, lipophilic (i.e., hydrophobic)surfactants are compounds having an HLB value equal to or less thanabout 10. However, HLB value of a surfactant is merely a rough guidegenerally used to enable formulation of industrial, pharmaceutical andcosmetic emulsions.

Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionicsurfactants include, but are not limited to, alkylammonium salts;fusidic acid salts; fatty acid derivatives of amino acids,oligopeptides, and polypeptides; glyceride derivatives of amino acids,oligopeptides, and polypeptides; lecithins and hydrogenated lecithins;lysolecithins and hydrogenated lysolecithins; phospholipids andderivatives thereof; lysophospholipids and derivatives thereof;carnitine fatty acid ester salts; salts of alkylsulfates; fatty acidsalts; sodium docusate; acylactylates; mono- and di-acetylated tartaricacid esters of mono- and di-glycerides; succinylated mono- anddi-glycerides; citric acid esters of mono- and di-glycerides; andmixtures thereof.

Within the aforementioned group, ionic surfactants include, by way ofexample: lecithins, lysolecithin, phospholipids, lysophospholipids andderivatives thereof; carnitine fatty acid ester salts; salts ofalkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono-and di-acetylated tartaric acid esters of mono- and di-glycerides;succinylated mono- and di-glycerides; citric acid esters of mono- anddi-glycerides; and mixtures thereof.

Ionic surfactants may be the ionized forms of lecithin, lysolecithin,phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol,phosphatidic acid, phosphatidylserine, lysophosphatidylcholine,lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidicacid, lysophosphatidylserine, PEG-phosphatidylethanolamine,PVP-phosphatidylethanol amine, lactylic esters of fatty acids,stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides,mono/diacetylated tartaric acid esters of mono/diglycerides, citric acidesters of mono/diglycerides, cholylsarcosine, caproate, caprylate,caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate,linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate,lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, andsalts and mixtures thereof.

Hydrophilic non-ionic surfactants may include, but not limited to,alkylglucosides; alkylmaltosides; alkylthioglucosides; laurylmacrogolglycerides; polyoxyalkylene alkyl ethers such as polyethyleneglycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethyleneglycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esterssuch as polyethylene glycol fatty acids monoesters and polyethyleneglycol fatty acids diesters; polyethylene glycol glycerol fatty acidesters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fattyacid esters such as polyethylene glycol sorbitan fatty acid esters;hydrophilic transesterification products of a polyol with at least onemember of the group consisting of glycerides, vegetable oils,hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylenesterols, derivatives, and analogues thereof; polyoxyethylated vitaminsand derivatives thereof; polyoxyethylene-polyoxypropylene blockcopolymers; and mixtures thereof; polyethylene glycol sorbitan fattyacid esters and hydrophilic transesterification products of a polyolwith at least one member of the group consisting of triglycerides,vegetable oils, and hydrogenated vegetable oils. The polyol may beglycerol, ethylene glycol, polyethylene glycol, sorbitol, propyleneglycol, pentaerythritol, or a saccharide.

Other hydrophilic-non-ionic surfactants include, without limitation,PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate,PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate,PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryllaurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenatedcastor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides,polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitanlaurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearylether, tocopheryl PEG-100 succinate, PEG-24 cholesterol,polyglyceryl-10oleate, Tween 40, Tween 60, sucrose monostearate, sucrosemonolaurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG15-100 octyl phenol series, and poloxamers.

Suitable lipophilic surfactants include, by way of example only: fattyalcohols; glycerol fatty acid esters; acetylated glycerol fatty acidesters; lower alcohol fatty acids esters; propylene glycol fatty acidesters; sorbitan fatty acid esters; polyethylene glycol sorbitan fattyacid esters; sterols and sterol derivatives; polyoxyethylated sterolsand sterol derivatives; polyethylene glycol alkyl ethers; sugar esters;sugar ethers; lactic acid derivatives of mono- and di-glycerides;hydrophobic transesterification products of a polyol with at least onemember of the group consisting of glycerides, vegetable oils,hydrogenated vegetable oils, fatty acids and sterols; oil-solublevitamins/vitamin derivatives; and mixtures thereof. Within this group,preferred lipophilic surfactants include glycerol fatty acid esters,propylene glycol fatty acid esters, and mixtures thereof, or arehydrophobic transesterification products of a polyol with at least onemember of the group consisting of vegetable oils, hydrogenated vegetableoils, and triglycerides.

In an embodiment, the composition may include a solubilizer to ensuregood solubilization and/or dissolution of the compound of the presentinvention and to minimize precipitation of the compound of the presentinvention. This can be especially important for compositions fornon-oral use—e.g., compositions for injection. A solubilizer may also beadded to increase the solubility of the hydrophilic drug and/or othercomponents, such as surfactants, or to maintain the composition as astable or homogeneous solution or dispersion.

Examples of suitable solubilizers include, but are not limited to, thefollowing: alcohols and polyols, such as ethanol, isopropanol, butanol,benzyl alcohol, ethylene glycol, propylene glycol, butanediols andisomers thereof, glycerol, pentaerythritol, sorbitol, mannitol,transcutol, dimethyl isosorbide, polyethylene glycol, polypropyleneglycol, polyvinylalcohol, hydroxypropyl methylcellulose and othercellulose derivatives, cyclodextrins and cyclodextrin derivatives;ethers of polyethylene glycols having an average molecular weight ofabout 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether(glycofurol) or methoxy PEG; amides and other nitrogen-containingcompounds such as 2-pyrrolidone, 2-piperidone, ϵ-caprolactam,N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone,N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esterssuch as ethyl propionate, tributylcitrate, acetyl triethylcitrate,acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate,ethyl butyrate, triacetin, propylene glycol monoacetate, propyleneglycol diacetate, .epsilon.-caprolactone and isomers thereof,δ-valerolactone and isomers thereof, β-butyrolactone and isomersthereof; and other solubilizers known in the art, such as dimethylacetamide, dimethyl isosorbide, N-methyl pyrrolidones, monooctanoin,diethylene glycol monoethyl ether, and water.

Mixtures of solubilizers may also be used. Examples include, but notlimited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate,dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone,polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol,transcutol, propylene glycol, and dimethyl isosorbide. Particularlypreferred solubilizers include sorbitol, glycerol, triacetin, ethylalcohol, PEG-400, glycofurol and propylene glycol.

The amount of solubilizer that can be included is not particularlylimited. The amount of a given solubilizer may be limited to abioacceptable amount, which may be readily determined by one of skill inthe art. In some circumstances, it may be advantageous to includeamounts of solubilizers far in excess of bioacceptable amounts, forexample to maximize the concentration of the drug, with excesssolubilizer removed prior to providing the composition to a patientusing conventional techniques, such as distillation or evaporation.Thus, if present, the solubilizer can be in a weight ratio of 10%, 25%,50%, 100%, or up to about 200% by weight, based on the combined weightof the drug, and other excipients. If desired, very small amounts ofsolubilizer may also be used, such as 5%, 2%, 1% or even less.Typically, the solubilizer may be present in an amount of about 1% toabout 100%, more typically about 5% to about 25% by weight.

The composition can further include one or more pharmaceuticallyacceptable additives and excipients. Such additives and excipientsinclude, without limitation, detackifiers, anti-foaming agents,buffering agents, polymers, antioxidants, preservatives, chelatingagents, viscomodulators, tonicifiers, flavorants, colorants, odorants,opacifiers, suspending agents, binders, fillers, plasticizers,lubricants, and mixtures thereof.

In addition, an acid or a base may be incorporated into the compositionto facilitate processing, to enhance stability, or for other reasons.Examples of pharmaceutically acceptable bases include amino acids, aminoacid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide,sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate,magnesium hydroxide, magnesium aluminum silicate, synthetic aluminumsilicate, synthetic hydrocalcite, magnesium aluminum hydroxide,diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine,triethylamine, triisopropanolamine, trimethylamine,tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable arebases that are salts of a pharmaceutically acceptable acid, such asacetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonicacid, amino acids, ascorbic acid, benzoic acid, boric acid, butyricacid, carbonic acid, citric acid, fatty acids, formic acid, fumaricacid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lacticacid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionicacid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinicacid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonicacid, uric acid, and the like. Salts of polyprotic acids, such as sodiumphosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphatecan also be used. When the base is a salt, the cation can be anyconvenient and pharmaceutically acceptable cation, such as ammonium,alkali metals and alkaline earth metals. Example may include, but notlimited to, sodium, potassium, lithium, magnesium, calcium and ammonium.

Suitable acids are pharmaceutically acceptable organic or inorganicacids. Examples of suitable inorganic acids include hydrochloric acid,hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boricacid, phosphoric acid, and the like. Examples of suitable organic acidsinclude acetic acid, acrylic acid, adipic acid, alginic acid,alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boricacid, butyric acid, carbonic acid, citric acid, fatty acids, formicacid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbicacid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid,para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid,salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid,thioglycolic acid, toluenesulfonic acid and uric acid.

Pharmaceutical Compositions for Injection

In preferred embodiments, the invention provides a pharmaceuticalcomposition for injection containing the combination of the PI3K, JAK-2,and BTK inhibitors, most preferably a combination of the JAK-2 and BTKinhibitors, and a pharmaceutical excipient suitable for injection.Components and amounts of agents in the compositions are as describedherein.

The forms in which the compositions of the present invention may beincorporated for administration by injection include aqueous or oilsuspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, orpeanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueoussolution, and similar pharmaceutical vehicles.

Aqueous solutions in saline are also conventionally used for injection.Ethanol, glycerol, propylene glycol and liquid polyethylene glycol (andsuitable mixtures thereof), cyclodextrin derivatives, and vegetable oilsmay also be employed. The proper fluidity can be maintained, forexample, by the use of a coating, such as lecithin, for the maintenanceof the required particle size in the case of dispersion and by the useof surfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid and thimerosal.

Sterile injectable solutions are prepared by incorporating thecombination of the PI3K, JAK-2, and BTK inhibitors in the requiredamounts in the appropriate solvent with various other ingredients asenumerated above, as required, followed by filtered sterilization.Generally, dispersions are prepared by incorporating the varioussterilized active ingredients into a sterile vehicle which contains thebasic dispersion medium and the required other ingredients from thoseenumerated above. In the case of sterile powders for the preparation ofsterile injectable solutions, certain desirable methods of preparationare vacuum-drying and freeze-drying techniques which yield a powder ofthe active ingredient plus any additional desired ingredient from apreviously sterile-filtered solution thereof.

Pharmaceutical Compositions for Topical Delivery

In preferred embodiments, the invention provides a pharmaceuticalcomposition for transdermal delivery containing the combination of thePI3K, JAK-2, and BTK inhibitors, most preferably a combination of theJAK-2 and BTK inhibitors, and a pharmaceutical excipient suitable fortransdermal delivery.

Compositions of the present invention can be formulated intopreparations in solid, semi-solid, or liquid forms suitable for local ortopical administration, such as gels, water soluble jellies, creams,lotions, suspensions, foams, powders, slurries, ointments, solutions,oils, pastes, suppositories, sprays, emulsions, saline solutions,dimethylsulfoxide (DMSO)-based solutions. In general, carriers withhigher densities are capable of providing an area with a prolongedexposure to the active ingredients. In contrast, a solution formulationmay provide more immediate exposure of the active ingredient to thechosen area.

The pharmaceutical compositions also may comprise suitable solid or gelphase carriers or excipients, which are compounds that allow increasedpenetration of, or assist in the delivery of, therapeutic moleculesacross the stratum corneum permeability barrier of the skin. There aremany of these penetration-enhancing molecules known to those trained inthe art of topical formulation. Examples of such carriers and excipientsinclude, but are not limited to, humectants (e.g., urea), glycols (e.g.,propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleicacid), surfactants (e.g., isopropyl myristate and sodium laurylsulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes(e.g., menthol), amines, amides, alkanes, alkanols, water, calciumcarbonate, calcium phosphate, various sugars, starches, cellulosederivatives, gelatin, and polymers such as polyethylene glycols.

Another exemplary formulation for use in the methods of the presentinvention employs transdermal delivery devices (“patches”). Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of the combination of the PI3K, JAK-2, and BTK inhibitors incontrolled amounts, either with or without another active pharmaceuticalingredient.

The construction and use of transdermal patches for the delivery ofpharmaceutical agents is well known in the art. See, e.g., U.S. Pat.Nos. 5,023,252; 4,992,445 and 5,001,139. Such patches may be constructedfor continuous, pulsatile, or on demand delivery of pharmaceuticalagents.

Pharmaceutical Compositions for Inhalation

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be inhaled directly from thenebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder compositions may be administered,preferably orally or nasally, from devices that deliver the formulationin an appropriate manner. Dry powder inhalers may also be used toprovide inhaled delivery of the compositions.

Other Pharmaceutical Compositions

Pharmaceutical compositions may also be prepared from compositionsdescribed herein and one or more pharmaceutically acceptable excipientssuitable for sublingual, buccal, rectal, intraosseous, intraocular,intranasal, epidural, or intraspinal administration. Preparations forsuch pharmaceutical compositions are well-known in the art. See, e.g.,Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds.,Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; andPratt and Taylor, eds., Principles of Drug Action, Third Edition,Churchill Livingston, N.Y., 1990, each of which is incorporated byreference herein in its entirety.

Administration of the combination of the PI3K, JAK-2, and BTK inhibitorsor pharmaceutical composition of these compounds can be effected by anymethod that enables delivery of the compounds to the site of action.These methods include oral routes, intraduodenal routes, parenteralinjection (including intravenous, intraarterial, subcutaneous,intramuscular, intravascular, intraperitoneal or infusion), topical(e.g., transdermal application), rectal administration, via localdelivery by catheter or stent or through inhalation. The combination ofcompounds can also be administered intraadiposally or intrathecally.

The compositions of the invention may also be delivered via animpregnated or coated device such as a stent, for example, or anartery-inserted cylindrical polymer. Such a method of administrationmay, for example, aid in the prevention or amelioration of restenosisfollowing procedures such as balloon angioplasty. Without being bound bytheory, compounds of the invention may slow or inhibit the migration andproliferation of smooth muscle cells in the arterial wall whichcontribute to restenosis. A compound of the invention may beadministered, for example, by local delivery from the struts of a stent,from a stent graft, from grafts, or from the cover or sheath of a stent.In some embodiments, a compound of the invention is admixed with amatrix. Such a matrix may be a polymeric matrix, and may serve to bondthe compound to the stent. Polymeric matrices suitable for such use,include, for example, lactone-based polyesters or copolyesters such aspolylactide, polycaprolactonglycolide, polyorthoesters, polyanhydrides,polyaminoacids, polysaccharides, polyphosphazenes, poly(ether-ester)copolymers (e.g. PEO-PLLA); polydimethylsiloxane,poly(ethylene-vinylacetate), acrylate-based polymers or copolymers(e.g., polyhydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone),fluorinated polymers such as polytetrafluoroethylene and celluloseesters. Suitable matrices may be nondegrading or may degrade with time,releasing the compound or compounds. The combination of the JAK-2, PI3K,and/or BTK inhibitors may be applied to the surface of the stent byvarious methods such as dip/spin coating, spray coating, dip-coating,and/or brush-coating. The compounds may be applied in a solvent and thesolvent may be allowed to evaporate, thus forming a layer of compoundonto the stent. Alternatively, the compound may be located in the bodyof the stent or graft, for example in microchannels or micropores. Whenimplanted, the compound diffuses out of the body of the stent to contactthe arterial wall. Such stents may be prepared by dipping a stentmanufactured to contain such micropores or microchannels into a solutionof the compound of the invention in a suitable solvent, followed byevaporation of the solvent. Excess drug on the surface of the stent maybe removed via an additional brief solvent wash. In yet otherembodiments, compounds of the invention may be covalently linked to astent or graft. A covalent linker may be used which degrades in vivo,leading to the release of the compound of the invention. Any bio-labilelinkage may be used for such a purpose, such as ester, amide oranhydride linkages. The combination of the PI3K, JAK-2, and BTKinhibitors may additionally be administered intravascularly from aballoon used during angioplasty. Extravascular administration of thecombination of the PI3K, JAK-2, and BTK inhibitors via the pericard orvia advential application of formulations of the invention may also beperformed to decrease restenosis.

Exemplary parenteral administration forms include solutions orsuspensions of active compound in sterile aqueous solutions, forexample, aqueous propylene glycol or dextrose solutions. Such dosageforms can be suitably buffered, if desired.

The invention also provides kits. The kits include each of the PI3K,JAK-2, and BTK inhibitors, either alone or in combination in suitablepackaging, and written material that can include instructions for use,discussion of clinical studies and listing of side effects. Such kitsmay also include information, such as scientific literature references,package insert materials, clinical trial results, and/or summaries ofthese and the like, which indicate or establish the activities and/oradvantages of the composition, and/or which describe dosing,administration, side effects, drug interactions, or other informationuseful to the health care provider. Such information may be based on theresults of various studies, for example, studies using experimentalanimals involving in vivo models and studies based on human clinicaltrials. The kit may further contain another active pharmaceuticalingredient. In selected embodiments, the PI3K, JAK-2, and BTK inhibitorsand another active pharmaceutical ingredient are provided as separatecompositions in separate containers within the kit. In selectedembodiments, the PI3K, JAK-2, and BTK inhibitors and the agent areprovided as a single composition within a container in the kit. Suitablepackaging and additional articles for use (e.g., measuring cup forliquid preparations, foil wrapping to minimize exposure to air, and thelike) are known in the art and may be included in the kit. Kitsdescribed herein can be provided, marketed and/or promoted to healthproviders, including physicians, nurses, pharmacists, formularyofficials, and the like. Kits may also, in selected embodiments, bemarketed directly to the consumer.

In some embodiments, the invention provides a kit comprising (1) acomposition comprising a therapeutically effective amount of a JAK-2inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof; and (2) a composition comprising atherapeutically effective amount of a BTK inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. These compositions are typically pharmaceuticalcompositions. The kit is for co-administration of the JAK-2 and the BTKinhibitors, either simultaneously or separately.

In some embodiments, the invention provides a kit comprising (1) acomposition comprising a therapeutically effective amount of a JAK-2inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof; (2) a composition comprising atherapeutically effective amount of a BTK inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; and (3) a composition comprising a therapeuticallyeffective amount of a PI3K inhibitor or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof. Thesecompositions are typically pharmaceutical compositions. The kit is forco-administration of the JAK-2, the BTK, and the PI3K inhibitors, eithersimultaneously or separately.

In some embodiments, the invention provides a kit comprising (1) acomposition comprising a therapeutically effective amount of a JAK-2inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof; (2) a composition comprising atherapeutically effective amount of a BTK inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; and (3) a composition comprising a therapeuticallyeffective amount of a PI3K-δ inhibitor or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof. Thesecompositions are typically pharmaceutical compositions. The kit is forco-administration of the JAK-2, the BTK, and the PI3K-δ inhibitors,either simultaneously or separately.

In some embodiments, the invention provides a kit comprising (1) acomposition comprising a therapeutically effective amount of JAK-2inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof; (2) a composition comprising atherapeutically effective amount of a BTK inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; and (3) a composition comprising a therapeuticallyeffective amount of an anti-CD20 antibody selected from the groupconsisting of rituximab, obinutuzumab, ofatumumab, veltuzumab,tositumomab, ibritumomab, and fragments, derivatives, conjugates,variants, radioisotope-labeled complexes, and biosimilars thereof. Thesecompositions are typically pharmaceutical compositions. The kit is forco-administration of the JAK-2 inhibitor, the BTK inhibitor, and theanti-CD20 antibody, either simultaneously or separately.

In some embodiments, the invention provides a kit comprising, (1) acomposition comprising a therapeutically effective amount of a JAK-2inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof; (2) a composition comprising atherapeutically effective amount of a BTK inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; (3) a composition comprising a therapeuticallyeffective amount of a PI3K inhibitor or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof; and (4) acomposition comprising a therapeutically effective amount of ananti-CD20 antibody selected from the group consisting of rituximab,obinutuzumab, ofatumumab, veltuzumab, tositumomab, ibritumomab, andfragments, derivatives, conjugates, variants, radioisotope-labeledcomplexes, and biosimilars thereof. These compositions are typicallypharmaceutical compositions. The kit is for co-administration of theJAK-2 inhibitor, the BTK inhibitor, and the anti-CD20 antibody, eithersimultaneously or separately.

In some embodiments, the invention provides a kit comprising, (1) acomposition comprising a therapeutically effective amount of a JAK-2inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof; (2) a composition comprising atherapeutically effective amount of a BTK inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; (3) a composition comprising a therapeuticallyeffective amount of a PI3K-δ inhibitor or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof; and (4) acomposition comprising a therapeutically effective amount of ananti-CD20 antibody selected from the group consisting of rituximab,obinutuzumab, ofatumumab, veltuzumab, tositumomab, ibritumomab, andfragments, derivatives, conjugates, variants, radioisotope-labeledcomplexes, and biosimilars thereof. These compositions are typicallypharmaceutical compositions. The kit is for co-administration of theJAK-2 inhibitor, the BTK inhibitor, the PI3K-δ inhibitor and theanti-CD20 antibody, either simultaneously or separately.

In some embodiments, the invention provides a kit comprising (1) acomposition comprising a therapeutically effective amount of a JAK-2inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof, (2) a composition comprising atherapeutically effective amount of a BTK inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; and (3) a composition comprising a therapeuticallyeffective amount of gemcitabine, albumin-bound paclitaxel, bendamustine,fludarabine, cyclophosphamide, chlorambucil, an anticoagulant orantiplatelet active pharmaceutical ingredient, or combinations thereof.These compositions are typically pharmaceutical compositions. The kit isfor co-administration of the JAK-2 inhibitor, BTK inhibitor,gemcitabine, albumin-bound paclitaxel, bendamustine, fludarabine,cyclophosphamide, chlorambucil, and/or the anticoagulant or theantiplatelet active pharmaceutical ingredient, either simultaneously orseparately.

In some embodiments, the invention provides a kit comprising, (1) acomposition comprising a therapeutically effective amount of a JAK-2inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof; (2) a composition comprising atherapeutically effective amount of a BTK inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; (3) a composition comprising a therapeuticallyeffective amount of a PI3K inhibitor or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof; and (4) acomposition comprising a therapeutically effective amount ofgemcitabine, albumin-bound paclitaxel, bendamustine, an anticoagulant orantiplatelet active pharmaceutical ingredient, or combinations thereof.These compositions are typically pharmaceutical compositions. The kit isfor co-administration of the JAK-2 inhibitor, BTK inhibitor, PI3Kinhibitor, gemcitabine, albumin-bound paclitaxel, bendamustine,fludarabine, cyclophosphamide, chlorambucil, and/or the anticoagulant orthe antiplatelet active pharmaceutical ingredient, either simultaneouslyor separately.

In some embodiments, the invention provides a kit comprising, (1) acomposition comprising a therapeutically effective amount of a JAK-2inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof; (2) a composition comprising atherapeutically effective amount of a BTK inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; (3) a composition comprising a therapeuticallyeffective amount of a PI3K-δ inhibitor or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof; and (4) acomposition comprising a therapeutically effective amount ofgemcitabine, albumin-bound paclitaxel, bendamustine, fludarabine,cyclophosphamide, chlorambucil, and/or an anticoagulant or antiplateletactive pharmaceutical ingredient. These compositions are typicallypharmaceutical compositions. The kit is for co-administration of theJAK-2 inhibitor, BTK inhibitor, PI3K-δ inhibitor, gemcitabine,albumin-bound paclitaxel, bendamustine, fludarabine, cyclophosphamide,chlorambucil, and/or the anticoagulant or the antiplatelet activepharmaceutical ingredient, either simultaneously or separately.

In some embodiments, the invention provides a kit comprising (1) acomposition comprising a therapeutically effective amount of a JAK-2inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof, (2) a composition comprising atherapeutically effective amount of a BTK inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; (3) a composition comprising a therapeuticallyeffective amount of an anti-CD20 antibody selected from the groupconsisting of rituximab, obinutuzumab, ofatumumab, veltuzumab,tositumomab, ibritumomab, and fragments, derivatives, conjugates,variants, radioisotope-labeled complexes, biosimilars thereof, andcombinations thereof; and (4) a composition comprising a therapeuticallyeffective amount of gemcitabine, albumin-bound paclitaxel, bendamustine,fludarabine, cyclophosphamide, chlorambucil, an anticoagulant orantiplatelet active pharmaceutical ingredient, or combinations thereof.These compositions are typically pharmaceutical compositions. The kit isfor co-administration of the JAK-2 inhibitor, BTK inhibitor, anti-CD20antibody, gemcitabine, albumin-bound paclitaxel, bendamustine,fludarabine, cyclophosphamide, chlorambucil, and/or the anticoagulant orthe antiplatelet active pharmaceutical ingredient, either simultaneouslyor separately.

In some embodiments, the invention provides a kit comprising, (1) acomposition comprising a therapeutically effective amount of a JAK-2inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof; (2) a composition comprising atherapeutically effective amount of a BTK inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; (3) a composition comprising a therapeuticallyeffective amount of a PI3K inhibitor or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof; (4) a compositioncomprising a therapeutically effective amount of an anti-CD20 antibodyselected from the group consisting of rituximab, obinutuzumab,ofatumumab, veltuzumab, tositumomab, ibritumomab, and fragments,derivatives, conjugates, variants, radioisotope-labeled complexes,biosimilars thereof, and combinations thereof; and (5) a compositioncomprising a therapeutically effective amount of gemcitabine,albumin-bound paclitaxel, bendamustine, fludarabine, cyclophosphamide,chlorambucil, and/or an anticoagulant or antiplatelet activepharmaceutical ingredient. These compositions are typicallypharmaceutical compositions. The kit is for co-administration of theJAK-2 inhibitor, BTK inhibitor, PI3K inhibitor, anti-CD20 antibody,gemcitabine, albumin-bound paclitaxel, bendamustine, fludarabine,cyclophosphamide, chlorambucil, and/or the anticoagulant or theantiplatelet active pharmaceutical ingredient, either simultaneously orseparately.

In some embodiments, the invention provides a kit comprising, (1) acomposition comprising a therapeutically effective amount of a JAK-2inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof; (2) a composition comprising atherapeutically effective amount of a BTK inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof; (3) a composition comprising a therapeuticallyeffective amount of a PI3K-δ inhibitor or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof; (4) a compositioncomprising a therapeutically effective amount of an anti-CD20 antibodyselected from the group consisting of rituximab, obinutuzumab,ofatumumab, veltuzumab, tositumomab, ibritumomab, and fragments,derivatives, conjugates, variants, radioisotope-labeled complexes,biosimilars thereof, and combinations thereof; and (5) a compositioncomprising a therapeutically effective amount of gemcitabine,albumin-bound paclitaxel, bendamustine, fludarabine, cyclophosphamide,chlorambucil, and/or an anticoagulant or antiplatelet activepharmaceutical ingredient. These compositions are typicallypharmaceutical compositions. The kit is for co-administration of theJAK-2 inhibitor, BTK inhibitor, PI3K-δ inhibitor, anti-CD20 antibody,gemcitabine, albumin-bound paclitaxel, bendamustine, fludarabine,cyclophosphamide, chlorambucil, and/or the anticoagulant or theantiplatelet active pharmaceutical ingredient, either simultaneously orseparately.

The kits described above are preferably for use in the treatment of thediseases and conditions described herein. In a preferred embodiment, thekits are for use in the treatment of cancer. In preferred embodiments,the kits are for use in treating solid tumor cancers, lymphomas andleukemias.

In a preferred embodiment, the kits of the present invention are for usein the treatment of cancer. In a preferred embodiment, the kits of thepresent invention are for use in the treatment of a cancer selected fromthe group consisting of bladder cancer, squamous cell carcinomaincluding head and neck cancer, pancreatic ductal adenocarcinoma (PDA),pancreatic cancer, colon carcinoma, mammary carcinoma, breast cancer,fibrosarcoma, mesothelioma, renal cell carcinoma, lung carcinoma,thyoma, prostate cancer, colorectal cancer, ovarian cancer, acutemyeloid leukemia, thymus cancer, brain cancer, squamous cell cancer,skin cancer, eye cancer, retinoblastoma, melanoma, intraocular melanoma,oral cavity and oropharyngeal cancers, gastric cancer, stomach cancer,cervical cancer, renal cancer, kidney cancer, liver cancer, ovariancancer, esophageal cancer, testicular cancer, gynecological cancer,thyroid cancer, aquired immune deficiency syndrome (AIDS)-relatedcancers (e.g., lymphoma and Kaposi's sarcoma), viral-induced cancer,glioblastoma, esophogeal tumors, hematological neoplasms, non-small-celllung cancer, chronic myelocytic leukemia, diffuse large B-cell lymphoma,esophagus tumor, follicle center lymphoma, head and neck tumor,hepatitis C virus infection, hepatocellular carcinoma, Hodgkin'sdisease, metastatic colon cancer, multiple myeloma, non-Hodgkin'slymphoma, indolent non-Hodgkin's lymphoma, ovary tumor, pancreas tumor,renal cell carcinoma, small-cell lung cancer, stage IV melanoma, chroniclymphocytic leukemia, B-cell acute lymphoblastic leukemia (ALL), matureB-cell ALL, follicular lymphoma, mantle cell lymphoma, and Burkitt'slymphoma.

Dosages and Dosing Regimens

The amounts of BTK inhibitors, PI3K inhibitors, and JAK-2 inhibitorsadministered will be dependent on the human or mammal being treated, theseverity of the disorder or condition, the rate of administration, thedisposition of the compounds and the discretion of the prescribingphysician. However, an effective dosage is in the range of about 0.001to about 100 mg per kg body weight per day, such as about 1 to about 35mg/kg/day, in single or divided doses. For a 70 kg human, this wouldamount to about 0.05 to 7 g/day, such as about 0.05 to about 2.5 g/day.In some instances, dosage levels below the lower limit of the aforesaidrange may be more than adequate, while in other cases still larger dosesmay be employed without causing any harmful side effect—e.g., bydividing such larger doses into several small doses for administrationthroughout the day. The dosage of BTK inhibitors, PI3K inhibitors, andJAK-2 inhibitors may be provided in units of mg/kg of body mass or inmg/m² of body surface area. In an embodiment, the ratio of the dose ofthe JAK-2 inhibitor to the dose of the BTK inhibitor in mg/kg or inmg/m² is in the range from 10:1 to 1:10, preferably from 2.5:1 to 1:2.5,and more preferably about 1:1. In an embodiment, the ratio of the doseof the JAK-2 inhibitor to the dose of the PI3K inhibitor in mg/kg or inmg/m² is in the range from 10:1 to 1:10, preferably from 2.5:1 to 1:2.5,and more preferably about 1:1. In an embodiment, the ratio of the JAK-2inhibitor to the BTK inhibitor in mg/kg or in mg/m² is selected from thegroup consisting of 20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1,12:1, 11:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3,1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16,1:17, 1:18, 1:19, and 1:20. In an embodiment, the weight ratio of theJAK-2 inhibitor to the PI3K inhibitor in mg/kg or in mg/m² is selectedfrom the group consisting of 20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1,13:1, 12:1, 11:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1,1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14,1:15, 1:16, 1:17, 1:18, 1:19, and 1:20.

In some embodiments, the combination of the PI3K, JAK-2, and/or BTKinhibitors is administered in a single dose. Such administration may beby injection, e.g., intravenous injection, in order to introduce thePI3K, JAK-2, and/or BTK inhibitors quickly. However, other routes,including the preferred oral route, may be used as appropriate. A singledose of the combination of the PI3K, JAK-2, and/or BTK inhibitors mayalso be used for treatment of an acute condition.

In some embodiments, the combination of the PI3K, JAK-2, and/or BTKinhibitors is administered in multiple doses. In a preferred embodiment,the combination of the JAK-2 and BTK inhibitors is administered inmultiple doses. Dosing may be once, twice, three times, four times, fivetimes, six times, or more than six times per day. Dosing may be once amonth, once every two weeks, once a week, or once every other day. Inother embodiments, the combination of the PI3K, JAK-2, and/or BTKinhibitors is administered about once per day to about 6 times per day.In some embodiments, the combination of the PI3K, JAK-2, and/or BTKinhibitors is administered once daily, while in other embodiments, thecombination of the PI3K, JAK-2, and/or BTK inhibitors is administeredtwice daily, and in other embodiments the combination of the PI3K,JAK-2, and/or BTK inhibitors is administered three times daily. In someembodiments, a BTK inhibitor disclosed herein is administered incombination with a PI3K-δ inhibitor and/or a JAK-2 inhibitor once daily,while in other embodiments a BTK inhibitor disclosed herein isadministered in combination with a PI3K-δ inhibitor and/or a JAK-2inhibitor twice daily, and in other embodiments a BTK inhibitordisclosed herein is administered in combination with a PI3K-δ inhibitorand/or a JAK-2 inhibitor three times daily. In some embodiments a PI3K-δinhibitor disclosed herein is administered in combination with a BTKinhibitor and/or a JAK-2 inhibitor once daily, while in otherembodiments a PI3K-δ inhibitor disclosed herein is administered incombination with a BTK inhibitor and/or a JAK-2 inhibitor twice daily,and in other embodiments a PI3K-δ inhibitor disclosed herein isadministered in combination with a BTK inhibitor and/or a JAK-2inhibitor three times daily. In some embodiments a JAK-2 inhibitordisclosed herein is administered in combination with a BTK inhibitorand/or a PI3K-δ inhibitor once daily, while in other embodiments a JAK-2inhibitor disclosed herein is administered in combination with a BTKinhibitor and/or a PI3K-δ inhibitor twice daily, and in otherembodiments a JAK-2 inhibitor disclosed herein is administered incombination with a BTK inhibitor and/or a PI3K-δ inhibitor three timesdaily.

Administration of the active pharmaceutical ingredients of the inventionmay continue as long as necessary. In selected embodiments, thecombination of the PI3K, JAK-2, and/or BTK inhibitors is administeredfor more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments,the combination of the PI3K, JAK-2, and BTK inhibitors is administeredfor less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In selectedembodiments, the combination of the PI3K, JAK-2, and/or BTK inhibitorsis administered chronically on an ongoing basis—e.g., for the treatmentof chronic effects. In another embodiment the administration of thecombination of the PI3K, JAK-2, and/or BTK inhibitors continues for lessthan about 7 days. In yet another embodiment the administrationcontinues for more than about 6, 10, 14, 28 days, two months, sixmonths, or one year. In some cases, continuous dosing is achieved andmaintained as long as necessary.

In some embodiments, an effective dosage of a BTK inhibitor disclosedherein is in the range of about 1 mg to about 500 mg, about 10 mg toabout 300 mg, about 20 mg to about 250 mg, about 25 mg to about 200 mg,about 10 mg to about 200 mg, about 20 mg to about 150 mg, about 30 mg toabout 120 mg, about 10 mg to about 90 mg, about 20 mg to about 80 mg,about 30 mg to about 70 mg, about 40 mg to about 60 mg, about 45 mg toabout 55 mg, about 48 mg to about 52 mg, about 50 mg to about 150 mg,about 60 mg to about 140 mg, about 70 mg to about 130 mg, about 80 mg toabout 120 mg, about 90 mg to about 110 mg, about 95 mg to about 105 mg,about 150 mg to about 250 mg, about 160 mg to about 240 mg, about 170 mgto about 230 mg, about 180 mg to about 220 mg, about 190 mg to about 210mg, about 195 mg to about 205 mg, or about 198 to about 202 mg. In someembodiments, an effective dosage of a BTK inhibitor disclosed herein isabout 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about150 mg, about 175 mg, about 200 mg, about 225 mg, or about 250 mg.

In some embodiments, an effective dosage of a BTK inhibitor disclosedherein is in the range of about 0.01 mg/kg to about 4.3 mg/kg, about0.15 mg/kg to about 3.6 mg/kg, about 0.3 mg/kg to about 3.2 mg/kg, about0.35 mg/kg to about 2.85 mg/kg, about 0.15 mg/kg to about 2.85 mg/kg,about 0.3 mg to about 2.15 mg/kg, about 0.45 mg/kg to about 1.7 mg/kg,about 0.15 mg/kg to about 1.3 mg/kg, about 0.3 mg/kg to about 1.15mg/kg, about 0.45 mg/kg to about 1 mg/kg, about 0.55 mg/kg to about 0.85mg/kg, about 0.65 mg/kg to about 0.8 mg/kg, about 0.7 mg/kg to about0.75 mg/kg, about 0.7 mg/kg to about 2.15 mg/kg, about 0.85 mg/kg toabout 2 mg/kg, about 1 mg/kg to about 1.85 mg/kg, about 1.15 mg/kg toabout 1.7 mg/kg, about 1.3 mg/kg mg to about 1.6 mg/kg, about 1.35 mg/kgto about 1.5 mg/kg, about 2.15 mg/kg to about 3.6 mg/kg, about 2.3 mg/kgto about 3.4 mg/kg, about 2.4 mg/kg to about 3.3 mg/kg, about 2.6 mg/kgto about 3.15 mg/kg, about 2.7 mg/kg to about 3 mg/kg, about 2.8 mg/kgto about 3 mg/kg, or about 2.85 mg/kg to about 2.95 mg/kg. In someembodiments, an effective dosage of a BTK inhibitor disclosed herein isabout 0.35 mg/kg, about 0.7 mg/kg, about 1 mg/kg, about 1.4 mg/kg, about1.8 mg/kg, about 2.1 mg/kg, about 2.5 mg/kg, about 2.85 mg/kg, about 3.2mg/kg, or about 3.6 mg/kg.

In some embodiments, an effective dosage of a PI3K inhibitor disclosedherein is in the range of about 1 mg to about 500 mg, about 10 mg toabout 300 mg, about 20 mg to about 250 mg, about 25 mg to about 200 mg,about 1 mg to about 50 mg, about 5 mg to about 45 mg, about 10 mg toabout 40 mg, about 15 mg to about 35 mg, about 20 mg to about 30 mg,about 23 mg to about 28 mg, about 50 mg to about 150 mg, about 60 mg toabout 140 mg, about 70 mg to about 130 mg, about 80 mg to about 120 mg,about 90 mg to about 110 mg, or about 95 mg to about 105 mg, about 98 mgto about 102 mg, about 150 mg to about 250 mg, about 160 mg to about 240mg, about 170 mg to about 230 mg, about 180 mg to about 220 mg, about190 mg to about 210 mg, about 195 mg to about 205 mg, or about 198 toabout 207 mg. In some embodiments, an effective dosage of a PI3Kinhibitor disclosed herein is about 25 mg, about 50 mg, about 75 mg,about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg,about 225 mg, or about 250 mg.

In some embodiments, an effective dosage of a PI3K inhibitor disclosedherein is in the range of about 0.01 mg/kg to about 4.3 mg/kg, about0.15 mg/kg to about 3.6 mg/kg, about 0.3 mg/kg to about 3.2 mg/kg, about0.35 mg/kg to about 2.85 mg/kg, about 0.01 mg/kg to about 0.7 mg/kg,about 0.07 mg/kg to about 0.65 mg/kg, about 0.15 mg/kg to about 0.6mg/kg, about 0.2 mg/kg to about 0.5 mg/kg, about 0.3 mg/kg to about 0.45mg/kg, about 0.3 mg/kg to about 0.4 mg/kg, about 0.7 mg/kg to about 2.15mg/kg, about 0.85 mg/kg to about 2 mg/kg, about 1 mg/kg to about 1.85mg/kg, about 1.15 mg/kg to about 1.7 mg/kg, about 1.3 mg/kg to about 1.6mg/kg, about 1.35 mg/kg to about 1.5 mg/kg, about 1.4 mg/kg to about1.45 mg/kg, about 2.15 mg/kg to about 3.6 mg/kg, about 2.3 mg/kg toabout 3.4 mg/kg, about 2.4 mg/kg to about 3.3 mg/kg, about 2.6 mg/kg toabout 3.15 mg/kg, about 2.7 mg/kg to about 3 mg/kg, about 2.8 mg/kg toabout 3 mg/kg, or about 2.85 mg/kg to about 2.95 mg/kg. In someembodiments, an effective dosage of a PI3K inhibitor disclosed herein isabout 0.4 mg/kg, about 0.7 mg/kg, about 1 mg/kg, about 1.4 mg/kg, about1.8 mg/kg, about 2.1 mg/kg, about 2.5 mg/kg, about 2.85 mg/kg, about 3.2mg/kg, or about 3.6 mg/kg.

In some embodiments, an effective dosage of a JAK-2 inhibitor disclosedherein is in the range of about 1 mg to about 500 mg, about 10 mg toabout 300 mg, about 20 mg to about 250 mg, about 25 mg to about 200 mg,about 1 mg to about 50 mg, about 5 mg to about 45 mg, about 10 mg toabout 40 mg, about 15 mg to about 35 mg, about 20 mg to about 30 mg,about 23 mg to about 28 mg, about 50 mg to about 150 mg, about 60 mg toabout 140 mg, about 70 mg to about 130 mg, about 80 mg to about 120 mg,about 90 mg to about 110 mg, or about 95 mg to about 105 mg, about 98 mgto about 102 mg, about 150 mg to about 250 mg, about 160 mg to about 240mg, about 170 mg to about 230 mg, about 180 mg to about 220 mg, about190 mg to about 210 mg, about 195 mg to about 205 mg, or about 198 toabout 207 mg. In some embodiments, an effective dosage of a JAK-2inhibitor disclosed herein is about 25 mg, about 50 mg, about 75 mg,about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg,about 225 mg, or about 250 mg.

In some embodiments, an effective dosage of a JAK-2 inhibitor disclosedherein is in the range of about 0.01 mg/kg to about 4.3 mg/kg, about0.15 mg/kg to about 3.6 mg/kg, about 0.3 mg/kg to about 3.2 mg/kg, about0.35 mg/kg to about 2.85 mg/kg, about 0.01 mg/kg to about 0.7 mg/kg,about 0.07 mg/kg to about 0.65 mg/kg, about 0.15 mg/kg to about 0.6mg/kg, about 0.2 mg/kg to about 0.5 mg/kg, about 0.3 mg/kg to about 0.45mg/kg, about 0.3 mg/kg to about 0.4 mg/kg, about 0.7 mg/kg to about 2.15mg/kg, about 0.85 mg/kg to about 2 mg/kg, about 1 mg/kg to about 1.85mg/kg, about 1.15 mg/kg to about 1.7 mg/kg, about 1.3 mg/kg to about 1.6mg/kg, about 1.35 mg/kg to about 1.5 mg/kg, about 1.4 mg/kg to about1.45 mg/kg, about 2.15 mg/kg to about 3.6 mg/kg, about 2.3 mg/kg toabout 3.4 mg/kg, about 2.4 mg/kg to about 3.3 mg/kg, about 2.6 mg/kg toabout 3.15 mg/kg, about 2.7 mg/kg to about 3 mg/kg, about 2.8 mg/kg toabout 3 mg/kg, or about 2.85 mg/kg to about 2.95 mg/kg. In someembodiments, an effective dosage of a JAK-2 inhibitor disclosed hereinis about 0.4 mg/kg, about 0.7 mg/kg, about 1 mg/kg, about 1.4 mg/kg,about 1.8 mg/kg, about 2.1 mg/kg, about 2.5 mg/kg, about 2.85 mg/kg,about 3.2 mg/kg, or about 3.6 mg/kg.

In some embodiments, a combination of a BTK inhibitor and a PI3Kinhibitor is adminstered at a dosage of 10 to 200 mg BID, including 50,60, 70, 80, 90, 100, 150, or 200 mg BID, for the BTK inhibitor, and 10to 200 mg BID, including 25, 50, 75, 100, 150, or 200 mg BID for thePI3K inhibitor.

In some embodiments, a combination of a BTK inhibitor and a JAK-2inhibitor is adminstered at a dosage of 10 to 200 mg BID, including 50,60, 70, 80, 90, 100, or 150 mg BID, for the BTK inhibitor, and 10 to 500mg BID, including 1, 5, 10, 15, 25, 50, 75, 100, 150, 200, 300, 400, or500 mg BID for the JAK-2 inhibitor.

In some embodiments, a combination of a PI3K inhibitor and a JAK-2inhibitor is adminstered at a dosage of 10 to 200 mg BID, including 50,60, 70, 80, 90, 100, or 150 mg BID, for the PI3K inhibitor, and 10 to500 mg BID, including 1, 5, 10, 15, 25, 50, 75, 100, 150, 200, 300, 400,or 500 mg BID for the JAK-2 inhibitor.

In some embodiments, a combination of a a BTK inhibitor, a PI3Kinhibitor, and a JAK-2 inhibitor is adminstered at a dosage of 10 to 200mg BID, including 50, 60, 70, 80, 90, 100, or 150 mg BID, for the BTKinhibitor, 10 to 200 mg BID, including 50, 60, 70, 80, 90, 100, or 150mg BID, for the PI3K inhibitor, and 10 to 500 mg BID, including 1, 5,10, 15, 25, 50, 75, 100, 150, 200, 300, 400, or 500 mg BID for the JAK-2inhibitor.

In some instances, dosage levels below the lower limit of the aforesaidranges may be more than adequate, while in other cases still largerdoses may be employed without causing any harmful side effect—e.g., bydividing such larger doses into several small doses for administrationthroughout the day.

An effective amount of the combination of the PI3K, JAK-2, and BTKinhibitors may be administered in either single or multiple doses by anyof the accepted modes of administration of agents having similarutilities, including rectal, buccal, intranasal and transdermal routes,by intra-arterial injection, intravenously, intraperitoneally,parenterally, intramuscularly, subcutaneously, orally, topically, or asan inhalant.

Methods of Treating Solid Tumor Cancers, Hematological Malignancies, andOther Diseases

The compositions and combinations of inhibitors described above can beused in a method for treating diseases. In a preferred embodiment, theyare for use in treating hyperproliferative disorders. They may also beused in treating other disorders as described herein and in thefollowing paragraphs.

In some embodiments, the invention provides a method of treating ahyperproliferative disorder in a mammal that comprises administering tosaid mammal a therapeutically effective amount of a PI3K inhibitor (or aPI3K-γ inhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) and a BTKinhibitor, or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug of either or both the PI3K inhibitor (or a PI3K-γinhibitor, PI3K-δ inhibitor, or PI3K-γ,δ inhibitor) or the BTKinhibitor. In some embodiments, the invention provides a method oftreating a hyperproliferative disorder in a mammal that comprisesadministering to said mammal a therapeutically effective amount of aJAK-2 inhibitor and a BTK inhibitor, or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug of either or both theJAK-2 inhibitor or the BTK inhibitor. In some embodiments, the inventionprovides a method of treating a hyperproliferative disorder in a mammalthat comprises administering to said mammal a therapeutically effectiveamount of a JAK-2 inhibitor and a PI3K inhibitor, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug of either orboth the JAK-2 inhibitor or the PI3K inhibitor. In some embodiments, theinvention provides a method of treating a hyperproliferative disorder ina mammal that comprises administering to said mammal a therapeuticallyeffective amount of a JAK-2 inhibitor, a BTK inhibitor, and a PI3Kinhibitor, or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug of the JAK-2 inhibitor, the BTK inhibitor, and/orthe PI3K inhibitor.

In some embodiments, the hyperproliferative disorder is cancer. Inselected embodiments, the cancer is selected from the group consistingof non-Hodgkin's lymphomas (such as diffuse large B-cell lymphoma),acute myeloid leukemia, thymus, brain, lung, squamous cell, skin, eye,retinoblastoma, intraocular melanoma, oral cavity and oropharyngeal,bladder, gastric, stomach, pancreatic, bladder, breast, cervical, head,neck, renal, kidney, liver, ovarian, prostate, colorectal, bone (e.g.,metastatic bone), esophageal, testicular, gynecological, thyroid, CNS,PNS, AIDS-related (e.g. lymphoma and Kaposi's sarcoma), viral-inducedcancers such as cervical carcinoma (human papillomavirus), B-celllymphoproliferative disease and nasopharyngeal carcinoma (Epstein-Barrvirus), Kaposi's sarcoma and primary effusion lymphomas (Kaposi'ssarcoma herpesvirus), hepatocellular carcinoma (hepatitis B andhepatitis C viruses), and T-cell leukemias (Human T-cell leukemiavirus-1), B cell acute lymphoblastic leukemia, Burkitt's leukemia,juvenile myelomonocytic leukemia, hairy cell leukemia, Hodgkin'sdisease, multiple myeloma, mast cell leukemia, and mastocytosis. Inselected embodiments, the method relates to the treatment of anon-cancerous hyperproliferative disorder such as benign hyperplasia ofthe skin (e.g., psoriasis), restenosis, or prostate conditions (e.g.,benign prostatic hypertrophy (BPH)).

In some embodiments, the hyperproliferative disorder is an inflammatory,immune, or autoimmune disorder. In some embodiments, thehyperproliferative disorder is selected from the group consisting oftumor angiogenesis, chronic inflammatory disease, rheumatoid arthritis,atherosclerosis, inflammatory bowel disease, skin diseases such aspsoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy,retinopathy of prematurity, age-related macular degeneration,hemangioma, glioma and melanoma, ulcerative colitis, atopic dermatitis,pouchitis, spondylarthritis, uveitis, Behcet's disease, polymyalgiarheumatica, giant-cell arteritis, sarcoidosis, Kawasaki disease,juvenile idiopathic arthritis, hidratenitis suppurativa, Sjögren'ssyndrome, psoriatic arthritis, juvenile rheumatoid arthritis, ankylosingspondylitis, Crohn's disease, lupus, and lupus nephritis.

In some embodiments, the invention provides pharmaceutical compositionsof a combination of a PI3K inhibitor, including a PI3K-γ, PI3K-δ, orPI3K-γ,δ inhibitor, a JAK-2 inhibitor, and/or a BTK inhibitor for thetreatment of disorders such as hyperproliferative disorder including butnot limited to cancer such as acute myeloid leukemia, thymus, brain,lung, squamous cell, skin, eye, retinoblastoma, intraocular melanoma,oral cavity and oropharyngeal, bladder, gastric, stomach, pancreatic,bladder, breast, cervical, head, neck, renal, kidney, liver, ovarian,prostate, colorectal, esophageal, testicular, gynecological, thyroid,CNS, PNS, AIDS-related (e.g., lymphoma and Kaposi's sarcoma) orviral-induced cancer. In some embodiments, said pharmaceuticalcomposition is for the treatment of a non-cancerous hyperproliferativedisorder such as benign hyperplasia of the skin (e.g., psoriasis),restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)).

In some embodiments, the invention provides pharmaceutical compositionsof a combination of a PI3K inhibitor, including a PI3K-γ, PI3K-δ, orPI3K-γ,δ inhibitor, a JAK-2 inhibitor, and/or a BTK inhibitor for thetreatment of disorders such as myeloproliferative disorders (MPDs),myeloproliferative neoplasms, polycythemia vera (PV), essentialthrombocythemia (ET), primary myelofibrosis (PMF), myelodysplasticsyndrome, chronic myelogenous leukemia (BCR-ABL1-positive), chronicneutrophilic leukemia, chronic eosinophilic leukemia, or mastocytosis.

The invention further provides a composition as described herein for theprevention of blastocyte implantation in a mammal.

The invention also provides a composition for treating a disease relatedto vasculogenesis or angiogenesis in a mammal which can manifest astumor angiogenesis, chronic inflammatory disease such as rheumatoidarthritis, inflammatory bowel disease, atherosclerosis, skin diseasessuch as psoriasis, eczema, and scleroderma, diabetes, diabeticretinopathy, retinopathy of prematurity, age-related maculardegeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma andovarian, breast, lung, pancreatic, prostate, colon and epidermoidcancer.

In one embodiment, provided herein is a method of treating, preventingand/or managing asthma. As used herein, “asthma” encompasses airwayconstriction regardless of the cause. Common triggers of asthma include,but are not limited to, exposure to an environmental stimulants (e.g.,allergens), cold air, warm air, perfume, moist air, exercise orexertion, and emotional stress. Also provided herein is a method oftreating, preventing and/or managing one or more symptoms associatedwith asthma. Examples of the symptoms include, but are not limited to,severe coughing, airway constriction and mucus production.

Efficacy of the compounds and combinations of compounds described hereinin treating, preventing and/or managing the indicated diseases ordisorders can be tested using various animal models known in the art.Efficacy in treating, preventing and/or managing asthma can be assessedusing the ova induced asthma model described, for example, in Lee, etal., J. Allergy Clin. Immunol. 2006, 118, 403-9. Efficacy in treating,preventing and/or managing arthritis (e.g., rheumatoid or psoriaticarthritis) can be assessed using the autoimmune animal models describedin, for example, Williams, et al., Chem. Biol. 2010, 17, 123-34, WO2009/088986, WO 2009/088880, and WO 2011/008302. Efficacy in treating,preventing and/or managing psoriasis can be assessed using transgenic orknockout mouse model with targeted mutations in epidermis, vasculatureor immune cells, mouse model resulting from spontaneous mutations, andimmuno-deficient mouse model with xenotransplantation of human skin orimmune cells, all of which are described, for example, in Boehncke, etal., Clinics in Dermatology, 2007, 25, 596-605. Efficacy in treating,preventing and/or managing fibrosis or fibrotic conditions can beassessed using the unilateral ureteral obstruction model of renalfibrosis, which is described, for example, in Chevalier, et al., KidneyInternational 2009, 75, 1145-1152; the bleomycin induced model ofpulmonary fibrosis described in, for example, Moore, et al., Am. J.Physiol. Lung. Cell. Mol. Physiol. 2008, 294, L152-L160; a variety ofliver/biliary fibrosis models described in, for example, Chuang, et al.,Clin. Liver Dis. 2008, 12, 333-347 and Omenetti, et al., LaboratoryInvestigation, 2007, 87, 499-514 (biliary duct-ligated model); or any ofa number of myelofibrosis mouse models such as described in Varicchio,et al., Expert Rev. Hematol. 2009, 2(3), 315-334. Efficacy in treating,preventing and/or managing scleroderma can be assessed using a mousemodel induced by repeated local injections of bleomycin described, forexample, in Yamamoto, et al., J. Invest. Dermatol. 1999, 112, 456-462.Efficacy in treating, preventing and/or managing dermatomyositis can beassessed using a myositis mouse model induced by immunization withrabbit myosin as described, for example, in Phyanagi, et al., Arthritis& Rheumatism, 2009, 60(10), 3118-3127. Efficacy in treating, preventingand/or managing lupus can be assessed using various animal modelsdescribed, for example, in Ghoreishi, et al., Lupus, 2009, 19,1029-1035; Ohl, et al., J. Biomed. Biotechnol., 2011, Article ID 432595;Xia, et al., Rheumatology, 2011, 50, 2187-2196; Pau, et al., PLoS ONE,2012, 7(5), e36761; Mustafa, et al., Toxicology, 2011, 290, 156-168;Ichikawa, et al., Arthritis & Rheumatism, 2012, 62(2), 493-503; Rankin,et al., J. Immunology, 2012, 188, 1656-1667. Efficacy in treating,preventing and/or managing Sjögren's syndrome can be assessed usingvarious mouse models described, for example, in Chiorini, et al., J.Autoimmunity, 2009, 33, 190-196.

In selected embodiments, the invention provides a method of treating asolid tumor cancer with a composition including a combination of a PI3Kinhibitor (e.g., a PI3K-γ or PI3K-δ inhibitor), a JAK-2 inhibitor,and/or a BTK inhibitor, wherein the dose is effective to inhibitsignaling between the solid tumor cells and at least onemicroenvironment selected from the group consisting of macrophages,monocytes, mast cells, helper T cells, cytotoxic T cells, regulatory Tcells, natural killer cells, myeloid-derived suppressor cells,regulatory B cells, neutrophils, dendritic cells, and fibroblasts. Inselected embodiments, the invention provides a method of treatingpancreatic cancer, breast cancer, ovarian cancer, melanoma, lung cancer,squamous cell carcinoma including head and neck cancer, and colorectalcancer using a combination of a BTK inhibitor, a PI3K inhibitor, and/ora JAK-2 inhibitor, wherein the dose is effective to inhibit signalingbetween the solid tumor cells and at least one microenvironment selectedfrom the group consisting of macrophages, monocytes, mast cells, helperT cells, cytotoxic T cells, regulatory T cells, natural killer cells,myeloid-derived suppressor cells, regulatory B cells, neutrophils,dendritic cells, and fibroblasts. In an embodiment, the inventionprovides a method for treating pancreatic cancer, breast cancer, ovariancancer, melanoma, lung cancer, head and neck cancer, and colorectalcancer using a combination of a BTK inhibitor, a PI3K inhibitor, and/ora JAK-2 inhibitor and gemcitabine, or a pharmaceutically-acceptablesalt, cocrystal, hydrate, solvate, or prodrug thereof. In an embodiment,the invention provides a method for treating pancreatic cancer, breastcancer, ovarian cancer, melanoma, lung cancer, head and neck cancer, andcolorectal cancer using a combination of a BTK inhibitor, a PI3Kinhibitor, and/or a JAK-2 inhibitor and gemcitabine, or apharmaceutically-acceptable salt, cocrystal, hydrate, solvate, orprodrug thereof, wherein the BTK inhibitor is a compound of Formula(XVIII). Efficacy of the compounds and combinations of compoundsdescribed herein in treating, preventing and/or managing the indicateddiseases or disorders can be tested using various models known in theart. For example, models for determining efficacy of treatments forpancreatic cancer are described in Herreros-Villanueva, et al., World J.Gastroenterol. 2012, 18, 1286-1294. Models for determining efficacy oftreatments for breast cancer are described, e.g., in Fantozzi, BreastCancer Res. 2006, 8, 212. Models for determining efficacy of treatmentsfor ovarian cancer are described, e.g., in Mullany, et al.,Endocrinology 2012, 153, 1585-92; and Fong, et al., J. Ovarian Res.2009, 2, 12. Models for determining efficacy of treatments for melanomaare described, e.g., in Damsky, et al., Pigment Cell & Melanoma Res.2010, 23, 853-859. Models for determining efficacy of treatments forlung cancer are described, e.g., in Meuwissen, et al., Genes &Development, 2005, 19, 643-664. Models for determining efficacy oftreatments for lung cancer are described, e.g., in Kim, Clin. Exp.Otorhinolaryngol. 2009, 2, 55-60; and Sano, Head Neck Oncol. 2009, 1,32. Models for determining efficacy of treatments for colorectal cancer,including the CT26 model, are described below in the examples.

Methods of Treating Patients Intolerant to Bleeding Events

In selected embodiments, the invention provides a method of treating acancer in a human sensitive to or intolerant to bleeding events,comprising the step of administering a therapeutically effective amountof a BTK inhibitor, or a pharmaceutically-acceptable salt, cocrystal,hydrate, solvate, or prodrug thereof, and a JAK-2 inhibitor and/or aPI3K inhibitor, or a pharmaceutically-acceptable salt, cocrystal,hydrate, solvate, or prodrug thereof. In a preferred embodiment, theinvention provides a method of treating a cancer in a human sensitive toor intolerant to bleeding events, comprising the step of administering atherapeutically effective amount of a BTK inhibitor, wherein the BTKinhibitor is selected from the group consisting of Formula (XVIII),Formula (XVIII-A), Formula (XVIII-B), Formula (XVIII-C), Formula(XVIII-D), and Formula (XVIII-E), and a pharmaceutically-acceptablesalt, cocrystal, hydrate, solvate, and prodrug thereof. In a preferredembodiment, the invention provides a method of treating a cancer in ahuman sensitive to or intolerant to bleeding events, comprising the stepof administering a therapeutically effective amount of a BTK inhibitorand a JAK-2 inhibitor, wherein the BTK inhibitor is selected from thegroup consisting of Formula (XVIII), Formula (XVIII-A), Formula(XVIII-B), Formula (XVIII-C), Formula (XVIII-D), and Formula (XVIII-E),and a pharmaceutically-acceptable salt, cocrystal, hydrate, solvate, andprodrug thereof, and wherein the JAK-2 inhibitor is selected from thegroup consisting of ruxolitinib, pacritinib, and apharmaceutically-acceptable salt, cocrystal, hydrate, solvate, andprodrug thereof.

In an embodiment, the invention provides a method of treating a cancerin a human intolerant to bleeding events, comprising the step ofadministering a therapeutically effective amount of a BTK inhibitor,wherein the BTK inhibitor is Formula (XVIII), or apharmaceutically-acceptable salt, cocrystal, hydrate, solvate, orprodrug thereof, and a JAK-2 inhibitor, or a pharmaceutically-acceptablesalt, cocrystal, hydrate, solvate, or prodrug thereof, furthercomprising the step of administering a therapeutically effective amountof an anticoagulant or antiplatelet active pharmaceutical ingredient.

In selected embodiments, the invention provides a method of treating acancer in a human intolerant to bleeding events, comprising the step ofadministering a therapeutically effective amount of a BTK inhibitor,wherein the BTK inhibitor is preferably a compound of Formula (XVIII),and wherein the cancer is selected from the group consisting of bladdercancer, squamous cell carcinoma including head and neck cancer,pancreatic ductal adenocarcinoma (PDA), pancreatic cancer, coloncarcinoma, mammary carcinoma, breast cancer, fibrosarcoma, mesothelioma,renal cell carcinoma, lung carcinoma, thyoma, prostate cancer,colorectal cancer, ovarian cancer, acute myeloid leukemia, thymuscancer, brain cancer, squamous cell cancer, skin cancer, eye cancer,retinoblastoma, melanoma, intraocular melanoma, oral cavity andoropharyngeal cancers, gastric cancer, stomach cancer, cervical cancer,head, neck, renal cancer, kidney cancer, liver cancer, colorectalcancer, esophageal cancer, testicular cancer, gynecological cancer,thyroid cancer, aquired immune deficiency syndrome (AIDS)-relatedcancers (e.g., lymphoma and Kaposi's sarcoma), viral-induced cancer,glioblastoma, esophogeal tumors, hematological neoplasms, non-small-celllung cancer, chronic myelocytic leukemia, diffuse large B-cell lymphoma,esophagus tumor, follicle center lymphoma, head and neck tumor,hepatitis C virus infection, hepatocellular carcinoma, Hodgkin'sdisease, metastatic colon cancer, multiple myeloma, non-Hodgkin'slymphoma, indolent non-Hogkin's lymphoma, ovary tumor, pancreas tumor,renal cell carcinoma, small-cell lung cancer, stage IV melanoma, chroniclymphocytic leukemia, B-cell acute lymphoblastic leukemia (ALL), matureB-cell ALL, follicular lymphoma, mantle cell lymphoma, and Burkitt'slymphoma.

In some embodiments, the invention provides a method of treating acancer in a human intolerant to platelet-mediated thrombosis comprisingthe step of administering a therapeutically effective amount of a BTKinhibitor, wherein the BTK inhibitor is Formula (XVIII), or apharmaceutically-acceptable salt, cocrystal, hydrate, solvate, orprodrug thereof, and a JAK-2 inhibitor, or a pharmaceutically-acceptablesalt, cocrystal, hydrate, solvate, or prodrug thereof.

In some embodiments, the BTK inhibitor and the anticoagulant or theantiplatelet active pharmaceutical ingredient are administeredsequentially. In some embodiments, the BTK inhibitor and theanticoagulant or the antiplatelet active pharmaceutical ingredient areadministered concomitantly. In selected embodiments, the BTK inhibitoris administered before the anticoagulant or the antiplatelet activepharmaceutical ingredient. In selected embodiments, the BTK inhibitor isadministered after the anticoagulant or the antiplatelet activepharmaceutical ingredient. In selected embodiments, a JAK-2 inhibitor isco-administered with the BTK inhibitor and the anticoagulant or theantiplatelet active pharmaceutical ingredient at the same time or atdifferent times.

Selected anti-platelet and anticoagulant active pharmaceuticalingredients for use in the methods of the present invention include, butare not limited to, cyclooxygenase inhibitors (e.g., aspirin), adenosinediphosphate (ADP) receptor inhibitors (e.g., clopidogrel andticlopidine), phosphodiesterase inhibitors (e.g., cilostazol),glycoprotein IIb/IIIa inhibitors (e.g., abciximab, eptifibatide, andtirofiban), and adenosine reuptake inhibitors (e.g., dipyridamole). Inother embodiments, examples of anti-platelet active pharmaceuticalingredients for use in the methods of the present invention includeanagrelide, aspirin/extended-release dipyridamole, cilostazol,clopidogrel, dipyridamole, prasugrel, ticagrelor, ticlopidine,vorapaxar, tirofiban HCl, eptifibatide, abciximab, argatroban,bivalirudin, dalteparin, desirudin, enoxaparin, fondaparinux, heparin,lepirudin, apixaban, dabigatran etexilate mesylate, rivaroxaban, andwarfarin.

In an embodiment, the invention provides a method of treating a cancer,comprising the step of orally administering, to a human in need thereof,a Bruton's tyrosine kinase (BTK) inhibitor, wherein the BTK inhibitor is(S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamideor a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, and a JAK-2 inhibitor, or pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof, furthercomprising the step of administering a therapeutically effective amountof an anticoagulant or antiplatelet active pharmaceutical ingredient,wherein the anticoagulant or antiplatelet active pharmaceuticalingredient is selected from the group consisting of acenocoumarol,anagrelide, anagrelide hydrochloride, abciximab, aloxiprin,antithrombin, apixaban, argatroban, aspirin, aspirin withextended-release dipyridamole, beraprost, betrixaban, bivalirudin,carbasalate calcium, cilostazol, clopidogrel, clopidogrel bisulfate,cloricromen, dabigatran etexilate, darexaban, dalteparin, dalteparinsodium, defibrotide, dicumarol, diphenadione, dipyridamole, ditazole,desirudin, edoxaban, enoxaparin, enoxaparin sodium, eptifibatide,fondaparinux, fondaparinux sodium, heparin, heparin sodium, heparincalcium, idraparinux, idraparinux sodium, iloprost, indobufen,lepirudin, low molecular weight heparin, melagatran, nadroparin,otamixaban, parnaparin, phenindione, phenprocoumon, prasugrel,picotamide, prostacyclin, ramatroban, reviparin, rivaroxaban,sulodexide, terutroban, terutroban sodium, ticagrelor, ticlopidine,ticlopidine hydrochloride, tinzaparin, tinzaparin sodium, tirofiban,tirofiban hydrochloride, treprostinil, treprostinil sodium, triflusal,vorapaxar, warfarin, warfarin sodium, ximelagatran, salts thereof,solvates thereof, hydrates thereof, prodrugs thereof, and combinationsthereof.

Combinations of BTK Inhibitors, PI3K Inhibitors, and JAK-2 Inhibitors

Non-limiting, exemplary embodiments of combinations of the PI3Kinhibitors, BTK inhibitors, and JAK-2 inhibitors described above aregiven in the following paragraphs. The disclosure encompassed hereinshould in no way be construed as being limited to these examples, butrather should be construed to encompass any and all variations whichbecome evident as a result of the teachings provided herein.

In an embodiment, the invention provides a method of treating leukemia,lymphoma, or a solid tumor cancer, comprising co-administering, to amammal in need thereof, a composition comprising therapeuticallyeffective amounts of (1) a PI3K inhibitor or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, (2) aJAK-2 inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof, and (3) a BTK inhibitor or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof.

In an embodiment, the invention provides a method of treating leukemia,lymphoma, or a solid tumor cancer, comprising co-administering, to amammal in need thereof, a composition comprising therapeuticallyeffective amounts of (1) a PI3K inhibitor or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and(2) a BTK inhibitor or a pharmaceutically acceptable salt, solvate,hydrate, cocrystal, or prodrug thereof.

In an embodiment, the invention provides a method of treating leukemia,lymphoma, or a solid tumor cancer, comprising co-administering, to amammal in need thereof, a composition comprising therapeuticallyeffective amounts of (1) a JAK-2 inhibitor or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and(2) a BTK inhibitor or a pharmaceutically acceptable salt, solvate,hydrate, cocrystal, or prodrug thereof.

In an embodiment, the invention provides the method as in any of thepreceding paragraphs, wherein the composition is administered by oral,intravenous, intramuscular, intraperitoneal, subcutaneous or transdermalmeans.

In an embodiment, the invention provides the method as in any of thepreceding paragraphs, wherein the PI3K inhibitor is a PI3K-γ inhibitor,a PI3K-δ inhibitor, or a PI3K-γ,δ inhibitor.

In an embodiment, the invention provides the method of any of thepreceding paragraphs, wherein the leukemia is selected from the groupconsisting of chronic lymphocytic leukemia, acute myeloid leukemia, andB cell acute lymphoblastic leukemia. In an embodiment, the inventionprovides the method of any of the preceding paragraphs, wherein thelymphoma is selected from the group consisting of Burkitt's lymphoma,mantle cell lymphoma, follicular lymphoma, indolent B-cell non-Hodgkin'slymphoma, histiocytic lymphoma, activated B-cell like diffuse large Bcell lymphoma, and germinal center B-cell like diffuse large B celllymphoma. In an embodiment, the invention provides the method of any ofthe preceding paragraphs, wherein the solid tumor cancer is selectedfrom the group consisting of breast, lung, colorectal, thyroid, bonesarcoma, and stomach cancers.

In an embodiment, the invention provides the method of any of thepreceding paragraphs, wherein the PI3K inhibitor is administered to thesubject before administration of the BTK inhibitor. In an embodiment,the invention provides the method of any of the preceding paragraphs,wherein the PI3K inhibitor is administered concurrently with theadministration of the BTK inhibitor. In an embodiment, the inventionprovides the method of any of preceding paragraphs, wherein the PI3Kinhibitor is administered to the subject after administration of the BTKinhibitor.

In an embodiment, the invention provides the method of any of thepreceding paragraphs, wherein the JAK-2 inhibitor is administered to thesubject before administration of the BTK inhibitor. In an embodiment,the invention provides the method of any of the preceding paragraphs,wherein the JAK-2 inhibitor is administered concurrently with theadministration of the BTK inhibitor. In an embodiment, the inventionprovides the method of any of the preceding paragraphs, wherein theJAK-2 inhibitor is administered to the subject after administration ofthe BTK inhibitor.

In an embodiment, the invention provides the method of any of thepreceding paragraphs, wherein the JAK-2 inhibitor is administered to thesubject before administration of the PI3K inhibitor. In an embodiment,the invention provides the method of any of the preceding paragraphs,wherein the JAK-2 inhibitor is administered concurrently with theadministration of the PI3K inhibitor. In an embodiment, the inventionprovides the method of any of the preceding paragraphs, wherein theJAK-2 inhibitor is administered to the subject after administration ofthe PI3K inhibitor.

In an embodiment, the invention provides the method of any of thepreceding paragraphs, wherein the PI3K inhibitor is a compound accordingto:

or any pharmaceutically-acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, wherein:X¹ is C(R⁹) or N;X² is C(R₁₀) or N;Y is N(R¹¹), O or S;Z is CR⁸ or N;n is 0, 1, 2 or 3;R¹ is a direct-bonded or oxygen-linked saturated, partially saturated orunsaturated 5-, 6- or 7-membered monocyclic ring containing 0, 1, 2, 3or 4 atoms selected from N, O and S, but containing no more than one 0or S, wherein the available carbon atoms of the ring are substituted by0, 1 or 2 oxo or thioxo groups, wherein the ring is substituted by 0 or1 R² substituents, and the ring is additionally substituted by 0, 1, 2or 3 substituents independently selected from halo, nitro, cyano,(C₁₋₄)alkyl, O(C₁₋₄)alkyl, O(C₁₋₄)haloalkyl, NH(C₁₋₄),N((C₁₋₄)alkyl)(C₁₋₄)alkyl and (C₁₋₄)haloalkyl;R² is selected from halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a). —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), OS(═O)R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)(C₂₋₆)alkylOR^(a); or R² is selected from(C₁₋₆)alkyl, phenyl, benzyl, heteroaryl, heterocycle,—((C₁₋₃)alkyl)heteroaryl, —((C₁₋₃)alkyl)heterocycle,—O((C₁₋₃)alkyl)heteroaryl, —O((C₁₋₃)alkyl)heterocycle,—NR^(a)((C₁₋₃)alkyl)heteroaryl, —NR^(a)((C₁₋₃)alkyl)heterocycle,—((C₁₋₃)alkyl)phenyl, —O((C₁₋₃)alkyl)phenyl and—NR^(a)((C₁₋₃)alkyl)phenyl all of which are substituted by 0, 1, 2 or 3substituents selected from (C₁₋₄)haloalkyl, O(C₁₋₄)alkyl, Br, Cl, F, Iand (C₁₋₄)alkyl;R³ is selected from H, halo, (C₁₋₄)haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)R^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R²,—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)NR^(a)R^(a),—NR^(a)(C₂₋₆)alkylOR^(a), (C₁₋₆)alkyl, phenyl, benzyl, heteroaryl andheterocycle, wherein the (C₁₋₆)alkyl, phenyl, benzyl, heteroaryl andheterocycle are additionally substituted by 0, 1, 2 or 3 substituentsselected from (C₁₋₆)haloalkyl, O(C₁₋₆)alkyl, Br, Cl, F, I and(C₁₋₆)alkyl;R⁴ is, independently, in each instance, halo, nitro, cyano, (C₁₋₄)alkyl,O(C₁₋₄)alkyl, O(C₁₋₄)haloalkyl, NH(C₁₋₄)alkyl, N((C₁₋₄)alkyl)(C₁₋₄)alkylor (C₁₋₄)haloalkyl;R⁵ is, independently, in each instance, H, halo, (C₁₋₆)alkyl,(C₁₋₄)haloalkyl, or (C₁₋₆)alkyl substituted by 1, 2 or 3 substituentsselected from halo, cyano, OH, O(C₁₋₄)alkyl, (C₁₋₄)alkyl,(C₁₋₃)haloalkyl, O(C₁₋₄)alkyl, NH₂, NH(C₁₋₄)alkyl,N((C₁₋₄)alkyl)(C₁₋₄)alkyl; or both R⁵ groups together form a(C₃₋₆)spiroalkyl substituted by 0, 1, 2 or 3 substituents selected fromhalo, cyano, OH, O(C₁₋₄)alkyl, (C₁₋₄)alkyl, (C₁₋₃)haloalkyl,O(C₁₋₄)alkyl, NH₂, NH(C₁₋₄)alkyl, N((C₁₋₄)alkyl)(C₁₋₄)alkyl;R⁶ is selected from H, halo, (C₁₋₆)alkyl, (C₁₋₄)haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—S(═O)R^(a), —S(O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a);R⁷ is selected from H, halo, (C₁₋₆)alkyl, (C₁₋₄)haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(a), —S(═O)₂N(R^(a))C(═O)OR^(a),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a);R⁸ is selected from H, (C₁₋₆)haloalkyl, Br, Cl, F, I, OR^(a),NR^(a)R^(a), (C₁₋₆)alkyl, phenyl, benzyl, heteroaryl and heterocycle,wherein the (C₁₋₆)alkyl, phenyl, benzyl, heteroaryl and heterocycle areadditionally substituted by 0, 1, 2 or 3 substituents selected from(C₁₋₆)haloalkyl, O(C₁₋₆)alkyl, Br, Cl, F, I and (C₁₋₆)alkyl;R⁹ is selected from H, halo, (C₁₋₄)haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a)C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—O(C₂₋₆)alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(O)NR^(a)R^(a)N(R^(a)C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₁₋₆alkyl, phenyl, benzyl, heteroaryl andheterocycle, wherein the (C₁₋₆)alkyl, phenyl, benzyl, heteroaryl andheterocycle are additionally substituted by 0, 1, 2 or 3 substituentsselected from halo, (C₁₋₄)haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—O(C₂₋₆)alkylNR^(a)R^(a), —O(C₂₋₆)alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)(C₂₋₆)alkylOR^(a), —NR^(a)(C₂₋₆)alkylOR^(a); or R⁹ is asaturated, partially-saturated or unsaturated 5-, 6- or 7-memberedmonocyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O andS, but containing no more than one O or S, wherein the available carbonatoms of the ring are substituted by 0, 1 or 2 oxo or thioxo groups,wherein the ring is substituted by 0, 1, 2, 3 or 4 substituents selectedfrom halo, (C₁₋₄)haloalkyl, cyano, nitro, —C(═O)R^(a), —C(═O)OR^(a),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—O(C₂₋₆)alkylNR^(a)R^(a), —O(C₂₋₆)alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)(C₂₋₆)alkylNR^(a)R^(a) and —NR^(a)(C₂₋₆)alkylOR^(a);R¹⁰ is H, (C₁₋₃)alkyl, (C₁₋₃)haloalkyl, cyano, nitro, CO₂R^(a),C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—S(═O)R^(b), S(═O)₂R^(b) or S(═O)₂NR^(a)R^(a);R¹¹ is H or (C₁₋₄)alkyl;R^(a) is independently, at each instance, H or R^(b); and R^(b) isindependently, at each instance, phenyl, benzyl or (C₁₋₆)alkyl, thephenyl, benzyl and (C₁₋₆)alkyl being substituted by 0, 1, 2 or 3substituents selected from halo, (C₁₋₄)alkyl, (C₁₋₃)haloalkyl,—O(C₁₋₄)alkyl, —NH₂, —NH(C₁₋₄)alkyl, —N((C₁₋₄)alkyl)(C₁₋₄)alkyl.

In an embodiment, the invention provides the method of any of thepreceding paragraphs, wherein the PI3K inhibitor is a compound accordingto:

or an enantiomer, a mixture of enantiomers, or a mixture of two or morediastereomers thereof, or a pharmaceutically acceptable salt, hydrate,solvate, cocrystal, or prodrug thereof, whereinCy is aryl or heteroaryl substituted by 0 or 1 occurrence of R³ and 0,1, 2, or 3 occurrence(s) of R⁵;W_(b) ⁵ is CR⁸, CHR⁸, or N;R⁸ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxylor nitro; B is hydrogen, alkyl, amino, heteroalkyl, cycloalkyl,heterocyclyl, aryl, or heteroaryl, each of which is substituted with 0,1, 2, 3, or 4 occurrence(s) of R²;each R² is independently alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo,cyano, hydroxyl, nitro, phosphate, urea, or carbonate;X is —(CH(R⁹))_(z)—;Y is —N(R⁹)—C(═O)—, —C(═O)—N(R⁹)—, —C(═O)—N(R⁹)—(CHR⁹)—, —N(R⁹)—S(═O)—,—S(═O)—N(R⁹)—, —S(═O)₂—N(R⁹)—, —N(R⁹)—C(═O)—N(R⁹) or —N(R⁹)S(═O)₂—;z is an integer of 1, 2, 3, or 4;R³ is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, fluoroalkyl,heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfinyl, sulfonyl,sulfoxide, sulfone, sulfonamido, halo, cyano, aryl, heteroaryl,hydroxyl, or nitro;each R⁵ is independently alkyl, alkenyl, alkynyl, cycloalkyl,heteroalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo,cyano, hydroxyl, or nitro;each R⁹ is independently hydrogen, alkyl, cycloalkyl, heterocyclyl, orheteroalkyl; or two adjacent occurrences of R⁹ together with the atomsto which they are attached form a 4- to 7-membered ring;W_(d) is heterocyclyl, aryl, cycloalkyl, or heteroaryl, each of which issubstituted with one or more R¹⁰, R¹¹, R¹² or R¹³, andR¹⁰, R¹¹, R¹² and R¹³ are each independently hydrogen, alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido,amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano,hydroxyl, nitro, phosphate, urea, carbonate or NR′R″ wherein R′ and R″are taken together with nitrogen to form a cyclic moiety.

In an embodiment, the invention provides the method of any of thepreceding paragraphs, wherein the PI3K inhibitor is a compound accordingto:

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, whereinB is:

wherein W_(c) is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, andq is an integer of 0, 1, 2, 3, or 4;X is a bond or —(CH(R⁹))_(z)—, and z is an integer of 1;Y is —N(R⁹)—;W_(d) is:

X₁, X₂ and X₃ are each independently C, CR¹³ or N; and X₄, X₅ and X₆ areeach independently N, NH, CR¹³, S or O;R¹ is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, amido, alkoxycarbonyl,sulfonamido, halo, cyano, or nitro;R² is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, heteroarylalkyl, alkoxy, amino, halo, cyano, hydroxy ornitro; R³ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, alkoxy, amido, amino, alkoxycarbonyl sulfonamido,halo, cyano, hydroxy or nitro; andeach instance of R⁹ is independently hydrogen, alkyl, orheterocycloalkyl.

In an embodiment, the invention provides the method of any of thepreceding paragraphs, wherein the BTK inhibitor is a compound accordingto:

or a pharmaceutically acceptable salt, hydrate, solvate, cocrystal, orprodrug thereof, whereinX is CH, N, O or S;Y is C(R₆), N, O or S;Z is CH, N or bond;A is CH or N;B₁ is N or C(R₇);B₂ is N or C(R₈);B₃ is N or C(R₉);B₄ is N or C(R₁₀);R₁ is R₁₁C(O), R₁₂S(O), R₁₃SO₂ or (C₁₋₆)alkyl optionally substitutedwith R₁₄;R₂ is H, (C₁₋₃)alkyl or (C₃₋₇)cycloalkyl;R₃ is H, (C₁₋₆)alkyl or (C₃₋₇)cycloalkyl; orR₂ and R₃ form, together with the N and C atom they are attached to, a(C₃₋₇)heterocycloalkyl optionally substituted with one or more fluorine,hydroxyl, (C₁₋₃)alkyl, (C₁₋₃)alkoxy or oxo;R₄ is H or (C₁₋₃)alkyl;R₅ is H, halogen, cyano, (C₁₋₄)alkyl, (C₁₋₃)alkoxy, (C₃₋₆)cycloalkyl,any alkyl group of which is optionally substituted with one or morehalogen; or R₅ is (C₆₋₁₀)aryl or (C₂₋₆)heterocycloalkyl;R₆ is H or (C₁₋₃)alkyl; orR₅ and R₆ together may form a (C₃₋₇)cycloalkenyl, or(C₂₋₆)heterocycloalkenyl; each optionally substituted with (C₁₋₃)alkyl,or one or more halogen;R₇ is H, halogen, CF₃, (C₁₋₃)alkyl or (C₁₋₃)alkoxy;

-   R₈ is H, halogen, CF₃, (C₁₋₃)alkyl or (C₁₋₃)alkoxy; or    R₇ and R₈ together with the carbon atoms they are attached to, form    (C₆₋₁₀)aryl or (C₁₋₉)heteroaryl;    R₉ is H, halogen, (C₁₋₃)alkyl or (C₁₋₃)alkoxy;    R₁₀ is H, halogen, (C₁₋₃)alkyl or (C₁₋₃)alkoxy;    R₁₁ is independently selected from a group consisting of    (C₁₋₆)alkyl, (C₁₋₆)alkenyl and (C₂₋₆)alkynyl each alkyl, alkenyl or    alkynyl optionally substituted with one or more groups selected from    hydroxyl, (C₁₋₄)alkyl, (C₃₋₇)cycloalkyl, [(C₁₋₄)alkyl]amino,    di[(C₁₋₄)alkyl]amino, (C₁₋₃)alkoxy, (C₃₋₇)cycloalkoxy, (C₆₋₁₀)aryl    or (C₃₋₇)heterocycloalkyl; or R₁₁ is (C₁₋₃)alkyl-C(O)—S—(C₁₋₃)alkyl;    or    R₁₁ is (C₁₋₅)heteroaryl optionally substituted with one or more    groups selected from halogen or cyano;    R₁₂ and R₁₃ are independently selected from a group consisting of    (C₂₋₆)alkenyl or (C₂₋₆)alkynyl both optionally substituted with one    or more groups selected from hydroxyl, (C₁₋₄)alkyl,    (C₃₋₇)cycloalkyl, [(C₁₋₄)alkyl]amino, di[(C₁₋₄)alkyl]amino,    (C₁₋₃)alkoxy, (C₃₋₇)cycloalkoxy, (C₆₋₁₀)aryl or    (C₃₋₇)heterocycloalkyl; or    (C₁₋₅)heteroaryl optionally substituted with one or more groups    selected from halogen or cyano; and    R₁₄ is independently selected from a group consisting of halogen,    cyano or (C₂₋₆)alkenyl or (C₂₋₆)alkynyl both optionally substituted    with one or more groups selected from hydroxyl, (C₁₋₄)alkyl,    (C₃₋₇)cycloalkyl, (C₁₋₄)alkylamino, di[(C₁₋₄)alkyl]amino,    (C₁₋₃)alkoxy, (C₃₋₇)cycloalkoxy, (C₆₋₁₀)aryl, (C₁₋₅)heteroaryl or    (C₃₋₇)heterocycloalkyl.

In an embodiment, the invention provides the method of any of thepreceding paragraphs, wherein the BTK inhibitor is a compound accordingto:

or a pharmaceutically acceptable salt, hydrate, solvate, cocrystal, orprodrug thereof, whereinL_(a) is CH₂, O, NH or S;Ar is a substituted or unsubstituted aryl, or a substituted orunsubstituted heteroaryl;Y is an optionally substituted group selected from the group consistingof alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl andheteroaryl;Z is C(═O), OC(═O), NRC(═O), C(═S), S(═O)_(x), OS(═O)_(x), NRS(═O)_(x),where x is 1 or 2;R₇ and R₈ are each H; or R₇ and R₈ taken together form a bond;R₆ is H; andR is H or (C₁-C₆)alkyl.

In an embodiment, the invention provides the method of any of thepreceding paragraphs, wherein the BTK inhibitor is a compound accordingto:

or a pharmaceutically acceptable salt, hydrate, solvate, cocrystal, orprodrug thereof, whereinL_(a) is CH₂, O, NH or S;Ar is a substituted or unsubstituted aryl, or a substituted orunsubstituted heteroaryl;Y is an optionally substituted group selected from the group consistingof alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl andheteroaryl;Z is C(═O), OC(═O), NRC(═O), C(═S), S(═O)_(x), OS(═O)_(x), NRS(═O)_(x),where x is 1 or 2;R₇ and R₈ are each H; or R₇ and R₈ taken together form a bond;R₆ is H; andR is H or (C₁-C₆)alkyl.

In an embodiment, the invention provides the method of any of thepreceding paragraphs, wherein the BTK inhibitor is a compound accordingto:

or a pharmaceutically acceptable salt, hydrate, solvate, cocrystal, orprodrug thereof, whereinL_(a) is CH₂, O, NH or S;Ar is a substituted or unsubstituted aryl, or a substituted orunsubstituted heteroaryl;Y is an optionally substituted group selected from the group consistingof alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl andheteroaryl;Z is C(═O), OC(═O), NRC(═O), C(═S), S(═O)_(x), OS(═O)_(x), NRS(═O)_(x),where x is 1 or 2;R₇ and R₈ are each H; or R₇ and R₈ taken together form a bond;R₆ is H; andR is H or (C₁-C₆)alkyl.

In an embodiment, the invention provides the method of any of thepreceding paragraphs, wherein the BTK inhibitor is a compound accordingto:

or a pharmaceutically acceptable salt, hydrate, solvate, cocrystal, orprodrug thereof, whereinL_(a) is CH₂, O, NH or S;Ar is a substituted or unsubstituted aryl, or a substituted orunsubstituted heteroaryl;Y is an optionally substituted group selected from the group consistingof alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl andheteroaryl;Z is C(═O), OC(═O), NRC(═O), C(═S), S(═O)_(x), OS(═O)_(x), NRS(═O)_(x),where x is 1 or 2;R₇ and R₈ are each H; or R₇ and R₈ taken together form a bond;R₆ is H; andR is H or (C₁-C₆)alkyl.

In an embodiment, the invention provides the method of any of thepreceding paragraphs, wherein the BTK inhibitor is a compound accordingto:

or a pharmaceutically acceptable salt, hydrate, solvate, cocrystal, orprodrug thereof, wherein:Q¹ is aryl¹, heteroaryl¹, cycloalkyl, heterocyclyl, cycloalkenyl, orheterocycloalkenyl, any of which is optionally substituted by one tofive independent G¹ substituents;R¹ is alkyl, cycloalkyl, bicycloalkyl, aryl, heteroaryl, aralkyl,heteroaralkyl, heterocyclyl, or heterobicycloalkyl, any of which isoptionally substituted by one or more independent G¹¹ substituents;G¹ and G⁴¹ are each independently halo, oxo, —CF₃, —OCF₃, —OR²,—NR²R³(R^(3a))_(j1), —C(O)R², —CO₂R², —CONR²R³, —NO₂, —CN, —S(O)_(j1)R²,—SO₂NR²R³, NR²(C═O)R³, NR²(C═O)OR³, NR²(C═O)NR²R³, NR²S(O)_(j1)R³,—(C═S)OR², —(C═O)SR, —NR²(C═NR³)NR^(2a)R^(3a), —NR²(C═NR³)OR^(2a),—NR²(C═NR³)SR^(3a), —O(C═O)OR², —O(C═O)NR²R³, —O(C═O)SR², —S(C═O)OR²,—S(C═O)NR²R³, (C₀₋₁₀)alkyl, (C₂₋₁₀)alkenyl, (C₂₋₁₀)alkynyl,(C₁₋₁₀)alkoxy(C₁₋₁₀)alkyl, (C₁₋₁₀)alkoxy(C₂₋₁₀)alkenyl,(C₁₋₁₀)alkoxy(C₂₋₁₀)alkynyl, (C₁₋₁₀)alkylthio(C₁₋₁₀)alkyl,(C₁₋₁₀)alkylthio(C₂₋₁₀)alkenyl, (C₁₋₁₀)alkylthio(C₂₋₁₀)alkynyl,cyclo(C₃₋₈)alkyl, cyclo(C₃₋₈)alkenyl, cyclo(C₃₋₈)alkyl(C₁₋₁₀)alkyl,cyclo(C₃₋₈)alkenyl(C₁₋₁₀)alkyl, cyclo(C₃₋₈)alkyl(C₂₋₁₀)alkenyl,cyclo(C₃₋₈)alkenyl(C₂₋₁₀)alkenyl, cyclo(C₃₋₈)alkyl(C₂₋₁₀)alkynyl,cyclo(C₃₋₈)alkenyl(C₂₋₁₀)alkynyl, heterocyclyl-(C₀₋₁₀)alkyl,heterocyclyl-(C₂₋₁₀)alkenyl, or heterocyclyl-(C₂₋₁₀)alkynyl, any ofwhich is optionally substituted with one or more independent halo, oxo,—CF₃, —OCF₃, —OR²²², —NR²²²R³³³(R³³³a)_(j1a), —C(O)R²²², —CO₂R²²²,—CONR²²²R³³³, —NO₂, —CN, —S(O)_(j1a)R²²², —SO₂NR²²²R³³³, NR²²²(C═O)R³³³,NR²²²(C═O)OR³³³, NR²²²(C═O)NR²²²R³³³, NR²²²S(O)_(j1a)R³³³, —(C═S)OR²²²,—(C═O)SR²²², —NR²²²(C═NR³³³)R^(222a)R^(333a), —NR²²²(C═NR³³³)OR^(222a),—NR²²²(C═NR³³³)SR^(333a), —O(C═O)OR²²², —O(C═O)NR²²²R³³³, —O(C═O)SR²²²,—S(C═O)OR²²², or —S(C═O)NR²²²R³³³ substituents; or—(X¹)_(n)—(Y¹)_(m)—R⁴; or aryl-(C₀₋₁₀)alkyl, aryl-(C₂₋₁₀)alkenyl, oraryl-(C₂₋₁₀)alkynyl, any of which is optionally substituted with one ormore independent halo, —CF₃, —OCF₃, —OR²²², —NR²²²R³³³(R^(333a))_(j2a),—C(O)R²²², —CO₂R²²², —CONR²²²R³³³, —NO₂, —CN, —S(O)_(j2a)R²²²,—SO₂NR²²²R³³³, NR²²²(C═O)R³³³, NR²²²(C═O)OR³³³, NR²²²(C═O)NR²²²R³³³,NR²²²S(O)_(j2a)R³³³, —(C═S)OR²²², —(C═O)SR²²²,—NR²²²(C═NR³³³)NR^(222a)R^(333a), —NR²²²(C═NR³³³)OR^(222a),—NR²²²(C═NR³³³)SR^(333a), —O(C═O)OR²²², —O(C═O)NR²²²R³³³, —O(C═O)SR²²²,—S(C═O)OR²²², or —S(C═O)NR²²²R³³³ substituents; or hetaryl-(C₀₋₁₀)alkyl,hetaryl-(C₂₋₁₀)alkenyl, or hetaryl-(C₂₋₁₀)alkynyl, any of which isoptionally substituted with one or more independent halo, —CF₃, —OCF₃,—OR²²², —NR²²², R³³³(R^(333a))_(j3a), —C(O)R²²², —CO₂R²²², —CONR²²²R³³³,—NO₂, —CN, —S(O)_(j3a)R²²², —SO₂NR²²²R³³³, NR²²²(C═O)R³³³,NR²²²(C═O)OR³³³, NR²²²(C═O)NR²²²R³³³, NR²²²S(O)_(j3a)R³³³, —(C═S)OR²²²,—(C═O)SR²²², —NR²²²(C═NR³³³)NR²²²aR³³³a, —NR²²²(C═NR³³³)OR^(222a),—NR²²²(C═NR³³³)SR³³³a, —O(C═O)OR²²², —O(C═O)NR²²²R³³³, —O(C═O)SR²²²,—S(C═O)OR²²², or —S(C═O)NR²²²R³³³ substituents;G¹¹ is halo, oxo, —CF₃, —OCF₃, —OR²¹, —NR²¹R³¹(R^(3a1))_(j4), —C(O)R²¹,—CO₂R²¹, —CONR²¹R³¹, —NO₂, —CN, —S(O)_(j4)R²¹, —SO₂NR²¹R³¹,NR²¹(C═O)R³¹, NR²¹(C═O)OR³¹, NR²¹(C═O)NR²¹R³¹, NR²¹S(O)_(j4)R³¹,—(C═S)OR²¹, —(C═O)SR²¹, —NR²¹ (C═NR³¹)NR^(2a1)R^(3a1),—NR²¹(C═NR³¹)OR^(2a1), —NR²¹(C═NR³¹)SR^(3a1), —O(C═O)OR²¹,—O(C═O)NR²¹R³¹, —O(C═O)SR²¹, —S(C═O)OR²¹, —S(C═O)NR²¹R³¹, —P(O)OR²¹OR³¹,(C₀₋₁₀)alkyl, (C₂₋₁₀)alkenyl, (C₂₋₁₀)alkynyl, (C₁₋₁₀)alkoxy(C₁₋₁₀)alkyl,(C₁₋₁₀)alkoxy(C₂₋₁₀)alkenyl, (C₁₋₁₀)alkoxy(C₂₋₁₀)alkynyl,(C₁₋₁₀)alkylthio(C₁₋₁₀)alkyl, (C₁₋₁₀)alkylthio(C₂₋₁₀)alkenyl,(C₁₋₁₀)alkylthio(C₂₋₁₀)alkynyl, cyclo(C₃₋₈)alkyl, cyclo(C₃₋₈)alkenyl,cyclo(C₃₋₈)alkyl(C₁₋₁₀)alkyl, cyclo(C₃₋₈)alkenyl(C₁₋₁₀)alkyl,cyclo(C₃₋₈)alkyl(C₂₋₁₀)alkenyl, cyclo(C₃₋₈)alkenyl(C₂₋₁₀)alkenyl,cyclo(C₃₋₈)alkyl(C₂₋₁₀)alkynyl, cyclo(C₃₋₈)alkenyl(C₂₋₁₀)alkynyl,heterocyclyl-(C₀₋₁₀)alkyl, heterocyclyl-(C₂₋₁₀)alkenyl, orheterocyclyl-(C₂₋₁₀)alkynyl, any of which is optionally substituted withone or more independent halo, oxo, —CF₃, —OCF₃, —OR²²²¹,NR²²²¹R³³³¹(R^(333a1))_(j4a), —C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹,—NO₂, —CN, —S(O)_(j4a)R²²²¹, —SO₂NR²²²¹R³³³¹, NR²²²¹(C═O)R³³³¹,NR²²²¹(C═O)OR³³³¹, NR²²²¹(C═O)NR²²²¹R³³³¹, NR²²²¹S(O)_(j4a)R³³³¹,—(C═S)OR²²²¹, —(C═O)SR²²²¹, —NR²²²¹(C═NR³³³¹)NR^(222a1)R^(333a1),—NR²²²¹(C═NR³³³¹)OR^(222a1), —NR²²²¹(C═NR³³³¹)SR^(333a1), —O(C═O)OR²²²¹,—O(C═O)NR²²²¹R³³³¹, —O(C═O)SR²²²¹, —S(C═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or—S(C═O)NR²²²¹R³³³¹ substituents; or aryl-(C₀₋₁₀)alkyl,aryl-(C₂₋₁₀)alkenyl, or aryl-(C₂₋₁₀)alkynyl, any of which is optionallysubstituted with one or more independent halo, —CF₃, —OCF₃, —OR²²²¹,—N²²²¹R³³³¹(R^(333a1))_(j5a), —C(O)R²²²¹, —CO₂R²²²¹, —CONR²²²¹R³³³¹,—NO₂, —CN, —S(O)_(j5a)R²²²¹, —SO₂NR²²²¹R³³³¹, NR²²²¹(C═O)R³³³¹,NR²²²¹(C═O)OR³³³¹, NR²²²¹(C═O)NR²²²¹R³³³¹, NR²²²¹S(O)_(j5a)R³³³¹,—(C═S)OR²²²¹, —(C═O)SR²²²¹, —NR²²²¹ (C═NR³³³¹)NR^(222a1)R^(333a1),—NR²²²¹(C═NR³³³¹)OR^(222a1), —NR²²²¹(C═NR³³³¹)SR^(333a1), —O(C═O)OR²²²¹,—O(C═O)NR²²²¹R³³³¹, —O(C═O)SR²²²¹, —S(C═O)OR²²²¹, —P(O)OR²²²¹R³³³¹, or—S(C═O)NR²²²¹R³³³¹ substituents; or hetaryl-(C₀₋₁₀)alkyl,hetaryl-(C₂₋₁₀)alkenyl, or hetaryl-(C₂₋₁₀)alkynyl, any of which isoptionally substituted with one or more independent halo, —CF₃, —OCF₃,—OR²²²¹, —NR²²²¹R³³³¹(R^(333a1))_(j6a), —C(O)R²²²¹, —C₂R²²²¹,—CONR²²²¹R³³³¹, —N₂, —CN, —S(O)_(j6a)R²²²¹, —SO₂NR²²²¹R³³³¹,NR²²²¹(C═O)R³³³¹, NR²²²¹(C═O)OR³³³¹, NR²²²¹(C═O)NR²²²¹R³³³¹,NR²²²¹S(O)_(j6a)R³³³¹, —(C═S)OR²²²¹, —(C═O)SR²²²¹,—NR²²²¹(C═NR³³³¹)NR^(222a1)R^(333a1), —NR²²²¹(C═NR³³³¹)OR^(222a1),—NR²²²¹(C═NR³³³¹)SR^(333a1), —O(C═O)OR²²²¹, —O(C═O)NR²²²¹R³³³¹,—O(C═O)SR²²²¹, —S(C═O)OR²²²¹, —P(O)OR²²²¹OR³³³¹, or —S(C═O)NR²²²¹R³³³¹substituents; or G¹¹ is taken together with the carbon to which it isattached to form a double bond which is substituted with R⁵ and G¹¹¹;R², R^(2a), R³, R^(3a), R²²², R²²²a, R³³³, R^(333a), R²¹, R^(2a1), R³¹,R^(3a1), R²²²¹, R^(222a1), R³³³¹, and R^(333a1) are each independentlyequal to (C₀₋₁₀)alkyl, (C₂₋₁₀)alkenyl, (C₂₋₁₀)alkynyl,(C₁₋₁₀)alkoxy(C₁₋₁₀)alkyl, (C₁₋₁₀)alkoxy(C₂₋₁₀)alkenyl,(C₁₋₁₀)alkoxy(C₂₋₁₀)alkynyl, (C₁₋₁₀)alkylthio(C₁₋₁₀)alkyl,(C₁₋₁₀)alkylthio(C₂₋₁₀)alkenyl, (C₁₋₁₀)alkylthio(C₂₋₁₀)alkynyl,cyclo(C₃₋₈)alkyl, cyclo(C₃₋₈)alkenyl, cyclo(C₃₋₈)alkyl(C₁₋₁₀)alkyl,cyclo(C₃₋₈)alkenyl(C₁₋₁₀)alkyl, cyclo(C₃₋₈)alkyl(C₂₋₁₀)alkenyl,cyclo(C₃₋₈)alkenyl(C₂₋₁₀)alkenyl, cyclo(C₃₋₈)alkyl(C₂₋₁₀)alkynyl,cyclo(C₃₋₈)alkenyl(C₂₋₁₀)alkynyl, heterocyclyl-(C₀₋₁₀)alkyl,heterocyclyl-(C₂₋₁₀)alkenyl, or heterocyclyl-(C₂₋₁₀)alkynyl, any ofwhich is optionally substituted by one or more G¹¹¹ substituents; oraryl-(C₀₋₁₀)alkyl, aryl-(C₂₋₁₀)alkenyl, or aryl-(C₂₋₁₀)alkynyl,hetaryl-(C₀₋₁₀)alkyl, hetaryl-(C₂₋₁₀)alkenyl, or hetaryl-(C₂₋₁₀)alkynyl,any of which is optionally substituted by one or more G¹¹¹ substituents;or in the case of —NR²R³(R^(3a))_(j1) or —NR²²²R³³³(R³³³a)_(j1)a or—NR²²²R³³³(R³³³a)j2a or —NR²²²¹R³³³¹(R^(333a1))_(j3a) or—NR²²²¹R³³³¹(R^(333a1))_(j4a) or —NR²²²¹R³³³¹(R^(333a1))_(j5a) or—NR²²²¹R³³³¹(R^(333a1))_(j6a), R² and R³ or R²²² and R³³³3 or R²²²¹ andR³³³¹ taken together with the nitrogen atom to which they are attachedform a 3-10 membered saturated ring, unsaturated ring, heterocyclicsaturated ring, or heterocyclic unsaturated ring, wherein said ring isoptionally substituted by one or more G¹¹¹ substituents;X¹ and Y¹ are each independently —O—, —NR⁷—, —S(O)_(j7)—, —CR⁵R⁶—,—N(C(O)OR⁷)—, —N(C(O)R⁷)—, —N(SO₂R⁷)—, —CH₂O—, —CH₂S—, —CH₂N(R⁷)—,—CH(NR⁷)—, —CH₂N(C(O)R⁷)—, —CH₂N(C(O)OR⁷)—, —CH₂N(SO₂R⁷)—, —CH(NHR⁷)—,—CH(NHC(O)R⁷)—, —CH(NHSO₂R⁷)—, —CH(NHC(O)OR⁷)—, —CHO(C(O)R⁷)—,—CHO(C(O)NHR⁷)—, —CH═CH—, —C.ident.C—, —C(═NOR⁷)—, —C(O)—, —CH(OR⁷)—,—C(O)N(R⁷)—, —N(R⁷)C(O)—, —N(R⁷)S(O)—, —N(R⁷)S(O)₂— —OC(O)N(R⁷)—,—N(R⁷)C(O)N(R⁷)—, —NR⁷C(O)O—, —S(O)N(R⁷)—, —S(O)₂N(R⁷)—,—N(C(O)R⁷)S(O)—, —N(C(O)R⁷)S(O)₂—, —N(R⁷)S(O)N(R⁷)—, —N(R⁷)S(O)₂N(R⁷)—,—C(O)N(R⁷)C(O)—, —S(O)N(R⁷)C(O)—, —S(O)₂N(R⁷)C(O)—, —OS(O)N(R⁷)—,—OS(O)₂N(R⁷)—, —N(R⁷)S(O)O—, —N(R⁷)S(O)₂O—, —N(R⁷)S(O)C(O)—,—N(R⁷)S(O)₂C(O)—, —SON(C(O)R⁷)—, —SO₂N(C(O)R⁷)—, —N(R⁷)SON(R⁷)—,—N(R⁷)SO₂N(R⁷)—, —C(O)O—, —N(R⁷)P(OR⁸)O—, —N(R⁷)P(OR⁸)—,—N(R⁷)P(O)(OR⁸)O—, —N(R⁷)P(O)(OR⁸)—, —N(C(O)R⁷)P(OR⁸)O—,—N(C(O)R⁷)P(OR⁸)—, —N(C(O)R⁷)P(O)(OR⁸)O—, —N(C(O)R⁷)P(OR⁸)—,—CH(R⁷)S(O)—, —CH(R⁷)S(O)₂—, —CH(R⁷)N(C(O)OR⁷)—, —CH(R⁷)N(C(O)R⁷)—,—CH(R⁷)N(SO₂R⁷)—, —CH(R⁷)O—, —CH(R⁷)S—, —CH(R⁷)N(R⁷)—,—CH(R⁷)N(C(O)R⁷)—, —CH(R⁷)N(C(O)OR⁷)—, —CH(R⁷)N(SO₂R⁷)—,—CH(R⁷)C(═NOR⁷)—, —CH(R⁷)C(O)—, —CH(R⁷)CH(OR⁷)—, —CH(R⁷)C(O)N(R⁷)—,—CH(R⁷)N(R⁷)C(O)—, —CH(R⁷)N(R⁷)S(O)—, —CH(R⁷)N(R⁷)S(O)₂—,—CH(R⁷)OC(O)N(R⁷)—, —CH(R⁷)N(R⁷)C(O)N(R⁷)—, —CH(R⁷)NR⁷C(O)O—,—CH(R⁷)S(O)N(R⁷)—, —CH(R⁷)S(O)₂N(R⁷)—, —CH(R⁷)N(C(O)R⁷)S(O)—,—CH(R⁷)N(C(O)R⁷)S(O)—, —CH(R⁷)N(R⁷)S(O)N(R⁷)—, —CH(R⁷)N(R⁷)S(O)₂N(R⁷)—,—CH(R⁷)C(O)N(R⁷)C(O)—, —CH(R⁷)S(O)N(R⁷)C(O)—, —CH(R⁷)S(O)₂N(R⁷)C(O)—,—CH(R⁷)OS(O)N(R⁷)—, —CH(R⁷)OS(O)₂N(R⁷)—, —CH(R⁷)N(R⁷)S(O)O—,—CH(R⁷)N(R⁷)S(O)₂O—, —CH(R⁷)N(R⁷)S(O)C(O)—, —CH(R⁷)N(R⁷)S(O)₂C(O)—,—CH(R⁷)SON(C(O)R⁷)—, —CH(R⁷)SO₂N(C(O)R⁷)—, —CH(R⁷)N(R⁷)SON(R⁷)—,—CH(R⁷)N(R⁷)SO₂N(R⁷)—, —CH(R⁷)C(O)O—, —CH(R⁷)N(R⁷)P(OR⁸)O—,—CH(R⁷)N(R⁷)P(OR⁸)—, —CH(R⁷)N(R⁷)P(O)(OR⁸)O—, —CH(R⁷)N(R⁷)P(o)(OR⁸)—,—CH(R⁷)N(C(O)R⁷)P(OR⁸)O—, —CH(R⁷)N(C(O)R⁷)P(OR⁸)—,—CH(R⁷)N(C(O)R⁷)P(O)(OR⁸)O—, or —CH(R⁷)N(C(O)R⁷)P(OR⁸)—; orX¹ and Y¹ are each independently represented by one of the followingstructural formulas:

R¹⁰, taken together with the phosphinamide or phosphonamide, is a 5-,6-, or 7-membered aryl, heteroaryl or heterocyclyl ring system;R⁵, R⁶, and G¹¹¹ are each independently a (C₀₋₁₀)alkyl, (C₂₋₁₀)alkenyl,(C₂₋₁₀)alkynyl, (C₁₋₁₀)alkoxy(C₁₋₁₀)alkyl, (C₁₋₁₀)alkoxy(C₂₋₁₀)alkenyl,(C₁₋₁₀)alkoxy(C₂₋₁₀)alkynyl, (C₁₋₁₀)alkylthio(C₁₋₁₀)alkyl,(C₁₋₁₀)alkylthio(C₂₋₁₀)alkenyl, (C₁₋₁₀)alkylthio(C₂₋₁₀)alkynyl,cyclo(C₃₋₈)alkyl, cyclo(C₃₋₈)alkenyl, cyclo(C₃₋₈)alkyl(C₁₋₁₀)alkyl,cyclo(C₃₋₈)alkenyl(C₁₋₁₀)alkyl, cyclo(C₃₋₈)alkyl(C₂₋₁₀)alkenyl,cyclo(C₃₋₈)alkenyl(C₂₋₁₀)alkenyl, cyclo(C₃₋₈)alkyl(C₂₋₁₀)alkynyl,cyclo(C₃₋₈)alkenyl(C₂₋₁₀)alkynyl, heterocyclyl-(C₀₋₁₀)alkyl,heterocyclyl-(C₂₋₁₀)alkenyl, or heterocyclyl-(C₂₋₁₀)alkynyl, any ofwhich is optionally substituted with one or more independent halo, —CF₃,—OCF₃, —OR⁷⁷, —NR⁷⁷R⁸⁷, —C(O)R⁷⁷, —CO₂R⁷⁷, —CONR⁷⁷R⁸⁷, —NO₂, —CN,—S(O)_(j5a)R⁷⁷, —SO₂NR⁷⁷R⁸⁷, NR⁷⁷(C═O)R⁸⁷, NR⁷⁷(C═O)OR⁸⁷,NR⁷⁷(C═O)NR⁷⁸R⁸⁷, NR⁷⁷S(O)_(j5a)R⁸⁷, —(C═S)OR⁷⁷, —(C═O)SR⁷⁷,—NR⁷⁷(C═NR⁸⁷)NR⁷⁸R⁸⁸, —NR⁷⁷(C═NR⁸⁷)OR⁷⁸, —NR⁷⁷(C═NR⁸⁷)SR⁷⁸, —O(C═O)OR⁷⁷,—O(C═O)NR⁷⁷R⁸⁷, —O(C═O)SR⁷⁷, —S(C═O)OR⁷⁷, —P(O)OR⁷⁷OR⁸⁷, or—S(C═O)NR⁷⁷R⁸⁷ substituents; or aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, oraryl-C₂₋₁₀alkynyl, any of which is optionally substituted with one ormore independent halo, —CF₃, —OCF₃, —OR⁷⁷, —NR⁷⁷R⁸⁷, —C(O)R⁷⁷, —CO₂R⁷⁷,—CONR⁷⁷R⁸⁷, —NO₂, —CN, —S(O)_(j5a)R⁷⁷, —SO₂NR⁷⁷R⁸⁷, NR⁷⁷(C═O)R⁸⁷,NR⁷⁷(C═O)OR⁸⁷, NR⁷⁷(C═O)NR⁷⁸R⁸⁷, NR⁷⁷S(O)_(j5a)R⁸⁷, —(C═S)OR⁷⁷,—(C═O)SR⁷⁷, —NR⁷⁷(C═NR⁸⁷)NR⁷⁸R⁸⁸, —NR⁷⁷(C═NR⁸⁷)OR⁷⁸, —NR⁷⁷(C═NR⁸⁷)SR⁷⁸,—O(C═O)OR⁷⁷, —O(C═O)NR⁷⁷R⁸⁷, —O(C═O)SR⁷⁷, —S(C═O)OR⁷⁷, —P(O)OR⁷⁷R⁸⁷, or—S(C═O)NR⁷⁷R⁸⁷ substituents; or hetaryl-(C₀₋₁₀)alkyl,hetaryl-(C₂₋₁₀)alkenyl, or hetaryl-(C₂₋₁₀)alkynyl, any of which isoptionally substituted with one or more independent halo, —CF₃, —OCF₃,—OR⁷⁷, —NR⁷⁷R⁸⁷, —C(O)R⁷⁷, —CO₂R⁷⁷, —CONR⁷⁷R⁸⁷, —NO₂, —CN,—S(O)_(j5a)R⁷⁷, —SO₂NR⁷⁷R⁸⁷, NR⁷⁷(C═O)R⁸⁷, NR⁷⁷(C═O)OR⁸⁷,NR⁷⁷(C═O)NR⁷⁸R⁸⁷, NR⁷⁷S(O)_(j5a)R⁸⁷, —(C═S)OR⁷⁷, —(C═O)SR⁷⁷,—NR⁷⁷(C═NR⁸⁷)NR⁷⁸R⁸⁸, —NR⁷⁷(C═NR⁸⁷)OR⁷⁸, —NR⁷⁷(C═NR⁸⁷)SR⁷⁸, —O(C═O)OR⁷⁷,—O(C═O)NR⁷⁷R⁸⁷, —O(C═O)SR⁷⁷, —S(C═O)OR⁷⁷, —P(O)OR⁷⁷OR⁸⁷, or—S(C═O)NR⁷⁷R⁸⁷ substituents; or R⁵ with R⁶ taken together with therespective carbon atom to which they are attached, form a 3-10 memberedsaturated or unsaturated ring, wherein said ring is optionallysubstituted with R⁶⁹; or R⁵ with R⁶ taken together with the respectivecarbon atom to which they are attached, form a 3-10 membered saturatedor unsaturated heterocyclic ring, wherein said ring is optionallysubstituted with R⁶⁹;R⁷ and R⁸ are each independently H, acyl, alkyl, alkenyl, aryl,heteroaryl, heterocyclyl or cycloalkyl, any of which is optionallysubstituted by one or more G¹¹¹ substituents;R⁴ is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl,heterocyclyl, cycloalkenyl, or heterocycloalkenyl, any of which isoptionally substituted by one or more G⁴¹ substituents;R⁶⁹ is equal to halo, —OR⁷⁸, —SH, —NR⁷⁸R⁸⁸, —CO₂R⁷⁸, —CONR⁷⁸R⁸⁸, —NO₂,—CN, —S(O)_(j8)R⁷⁸, —SO₂NR⁷⁸R⁸⁸, (C₀₋₁₀)alkyl, (C₂₋₁₀)alkenyl,(C₂₋₁₀)alkynyl, (C₁₋₁₀)alkoxy(C₁₋₁₀)alkyl, (C₁₋₁₀)alkoxy(C₂₋₁₀)alkenyl,(C₁₋₁₀)alkoxy(C₂₋₁₀)alkynyl, (C₁₋₁₀)alkylthio(C₁₋₁₀)alkyl,(C₁₋₁₀)alkylthio(C₂₋₁₀)alkenyl, (C₁₋₁₀)alkylthio(C₂₋₁₀)alkynyl,cyclo(C₃₋₈)alkyl, cyclo(C₃₋₈)alkenyl, cyclo(C₃₋₈)alkyl(C₁₋₁₀)alkyl,cyclo(C₃₋₈)alkenyl(C₁₋₁₀)alkyl, cyclo(C₃₋₈)alkyl(C₂₋₁₀)alkenyl,cyclo(C₃₋₈)alkenyl(C₂₋₁₀)alkenyl, cyclo(C₃₋₈)alkyl(C₂₋₁₀)alkynyl,cyclo(C₃₋₈)alkenyl(C₂₋₁₀)alkynyl, heterocyclyl-(C₀₋₁₀)alkyl,heterocyclyl-(C₂₋₁₀)alkenyl, or heterocyclyl-(C₂₋₁₀)alkynyl, any ofwhich is optionally substituted with one or more independent halo,cyano, nitro, —OR⁷⁷⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸, or —NR⁷⁷⁸R⁸⁸⁸ substituents; oraryl-(C₀₋₁₀)alkyl, aryl-(C₂₋₁₀)alkenyl, or aryl-(C₂₋₁₀)alkynyl, any ofwhich is optionally substituted with one or more independent halo,cyano, nitro, —OR⁷⁷⁸, (C₁₋₁₀)alkyl, (C₂₋₁₀)alkenyl, (C₂₋₁₀)alkynyl,halo(C₁₋₁₀)alkyl, haloC₂₋₁₀alkenyl, haloC₂₋₁₀alkynyl, —COOH,(C₁₋₄)alkoxycarbonyl, —CONR⁷⁸⁸R⁸⁸⁸, —SO₂NR⁷⁷⁸R⁸⁸⁸, or —NR⁷⁷⁸R⁸⁸⁸substituents; or hetaryl-(C₀₋₁₀)alkyl, hetaryl-(C₂₋₁₀)alkenyl, orhetaryl-(C₂₋₁₀)alkynyl, any of which is optionally substituted with oneor more independent halo, cyano, nitro, —OR⁷⁷⁸, (C₁₋₁₀)alkyl,(C₂₋₁₀)alkenyl, (C₂₋₁₀)alkynyl, halo(C₁₋₁₀)alkyl, halo(C₂₋₁₀)alkenyl,halo(C₂₋₁₀)alkynyl, —COOH, (C₁₋₄)alkoxycarbonyl, —CONR⁷⁷⁸R⁸⁸⁸,—SO₂NR⁷⁷⁸R⁸⁸⁸, or —NR⁷⁷⁸R⁸⁸⁸ substituents; ormono((C₁₋₆)alkyl)amino(C₁₋₆)alkyl, di((C₁₋₆)alkyl)amino(C₁₋₆)alkyl,mono(aryl)amino(C₁₋₆)alkyl, di(aryl)amino(C₁₋₆)alkyl, or—N((C₁₋₆)alkyl)-(C₁₋₆)alkyl-aryl, any of which is optionally substitutedwith one or more independent halo, cyano, nitro, —OR⁷⁷⁸, (C₁₋₁₀)alkyl,(C₂₋₁₀)alkenyl, (C₂₋₁₀)alkynyl, halo(C₁₋₁₀)alkyl, halo(C₂₋₁₀)alkenyl,halo(C₂₋₁₀)alkynyl, —COOH, (C₁₋₄)alkoxycarbonyl,—CONR⁷⁷⁸R⁸⁸⁸SO₂NR⁷⁷⁸R⁸⁸⁸, or —NR⁷⁷⁸R⁸⁸⁸ substituents; or in the case of—NR⁷⁸R⁸⁸, R⁷⁸ and R⁸⁸ taken together with the nitrogen atom to whichthey are attached form a 3-10 membered saturated ring, unsaturated ring,heterocyclic saturated ring, or heterocyclic unsaturated ring, whereinsaid ring is optionally substituted with one or more independent halo,cyano, hydroxy, nitro, (C₁₋₁₀)alkoxy, —SO₂NR⁷⁷⁸R⁸⁸⁸, or —NR⁷⁷⁸R⁸⁸⁸substituents;R⁷⁷, R⁷⁸, R⁸⁷, R⁸⁸, R⁷⁷⁸, and R⁸⁸⁸ are each independently (C₀₋₁₀)alkyl,(C₂₋₁₀)alkenyl, (C₂₋₁₀)alkynyl, (C₁₋₁₀)alkoxy(C₁₋₁₀)alkyl,(C₁₋₁₀)alkoxy(C₂₋₁₀)alkenyl, (C₁₋₁₀)alkoxy(C₂₋₁₀)alkynyl,(C₁₋₁₀)alkylthio(C₁₋₁₀)alkyl, (C₁₋₁₀)alkylthio(C₂₋₁₀)alkenyl,(C₁₋₁₀)alkylthio(C₂₋₁₀)alkynyl, cyclo(C₃₋₈)alkyl, cyclo(C₃₋₈)alkenyl,cyclo(C₃₋₈)alkyl(C₁₋₁₀)alkyl, cyclo(C₃₋₈)alkenyl(C₁₋₁₀)alkyl,cyclo(C₃₋₈)alkyl(C₂₋₁₀)alkenyl, cyclo(C₃₋₈)alkenyl(C₂₋₁₀)alkenyl,cyclo(C₃₋₈)alkyl(C₂₋₁₀)alkynyl, cyclo(C₃₋₈)alkenyl(C₂₋₁₀)alkynyl,heterocyclyl-(C₀₋₁₀)alkyl, heterocyclyl-(C₂₋₁₀)alkenyl,heterocyclyl-(C₂₋₁₀)alkynyl, (C₁₋₁₀)alkylcarbonyl,(C₂₋₁₀)alkenylcarbonyl, (C₂₋₁₀)alkynylcarbonyl, (C₁₋₁₀)alkoxycarbonyl,(C₁₋₁₀)alkoxycarbonyl(C₁₋₁₀)alkyl, mono(C₁₋₆)alkylaminocarbonyl,di(C₁₋₆)alkylaminocarbonyl, mono(aryl)aminocarbonyl,di(aryl)aminocarbonyl, or (C₁₋₁₀)alkyl(aryl)aminocarbonyl, any of whichis optionally substituted with one or more independent halo, cyano,hydroxy, nitro, (C₁₋₁₀)alkoxy, —SO₂N((C₀₋₄)alkyl)((C₀₋₄)alkyl), or—N((C₀₋₄)alkyl)((C₀₋₄)alkyl) substituents; or aryl-(C₀₋₁₀)alkyl,aryl-(C₂₋₁₀)alkenyl, or aryl-(C₂₋₁₀)alkynyl, any of which is optionallysubstituted with one or more independent halo, cyano, nitro,—O((C₀₋₄)alkyl), (C₁₋₁₀)alkyl, (C₂₋₁₀)alkenyl, (C₂₋₁₀)alkynyl,halo(C₁₋₁₀)alkyl, halo(C₂₋₁₀)alkenyl, halo(C₂₋₁₀)alkynyl, —COOH,(C₁₋₄)alkoxycarbonyl, —CON((C₀₋₄)alkyl)((C₀₋₁₀)alkyl),—SO₂N((C₀₋₄)alkyl)((C₀₋₄)alkyl), or —N((C₀₋₄)alkyl)((C₀₋₄)alkyl)substituents; or hetaryl-(C₀₋₁₀)alkyl, hetaryl-(C₂₋₁₀)alkenyl, orhetaryl-(C₂₋₁₀)alkynyl, any of which is optionally substituted with oneor more independent halo, cyano, nitro, —O((C₀₋₄)alkyl), (C₁₋₁₀)alkyl,(C₂₋₁₀)alkenyl, (C₂₋₁₀)alkynyl, halo(C₁₋₁₀)alkyl, halo(C₂₋₁₀)alkenyl,halo(C₂₋₁₀)alkynyl, —COOH, (C₁₋₄)alkoxycarbonyl,—CON((C₀₋₄)alkyl)((C₀₋₄)alkyl), —SO₂N((C₀₋₄)alkyl)((C₀₋₄)alkyl), or—N((C₀₋₄)alkyl)((C₀₋₄)alkyl) substituents; ormono((C₁₋₆)alkyl)amino(C₁₋₆)alkyl, di((C₁₋₆)alkyl)amino(C₁₋₆)alkyl,mono(aryl)amino(C₁₋₆)alkyl, di(aryl)amino(C₁₋₆)alkyl, or—N((C₁₋₆)alkyl)-(C₁₋₆)alkyl-aryl, any of which is optionally substitutedwith one or more independent halo, cyano, nitro, —O((C₀₋₄)alkyl),(C₁₋₁₀)alkyl, (C₂₋₁₀)alkenyl, (C₂₋₁₀)alkynyl, halo(C₁₋₁₀)alkyl,halo(C₂₋₁₀)alkenyl, halo(C₂₋₁₀)alkynyl, —COOH, (C₁₋₄)alkoxycarbonyl,—CON((C₀₋₄)alkyl)((C₀₋₄)alkyl), —SO₂N((C₀₋₄)alkyl)((C₀₋₄)alkyl), or—N((C₀₋₄)alkyl)((C₀₋₄)alkyl) substituents; andn, m, j1, j1a, j2a, j3a, j4, j4a, j5a, j6a, j7, and j8 are eachindependently equal to 0, 1, or 2.

In an embodiment, the invention provides the method of any of thepreceding paragraphs, wherein the BTK inhibitor is a compound accordingto:

or a pharmaceutically acceptable salt, hydrate, solvate, cocrystal, orprodrug thereof, whereinL represents (1) —O—, (2) —S—, (3) —SO—, (4) —SO₂— (5) —NH—, (6) —C(O)—,(7) —CH₂O—, (8) —O—CH₂—, (9) —CH₂—, or (10) —CH(OH)—;R¹ represents (1) a halogen atom, (2) a C₁₋₄ alkyl group, (3) a C₁₋₄alkoxy group, (4) a C₁₋₄ haloalkyl group, or (5) a C₁₋₄ haloalkoxygroup;ring1 represents a 4- to 7-membered cyclic group, which may besubstituted by from one to five substituents each independently selectedfrom the group consisting of (1) halogen atoms, (2) C₁₋₄ alkyl groups,(3) C₁₋₄ alkoxy groups, (4) nitrile, (5) C₁₋₄ haloalkyl groups, and (6)C₁₋₄ haloalkoxy groups, wherein when two or more substituents arepresent on ring1, these substituents may form a 4- to 7-membered cyclicgroup together with the atoms in ring1 to which these substituents arebound;ring2 represents a 4- to 7-membered saturated heterocycle, which may besubstituted by from one to three -K-R²; K represents (1) a bond, (2) aC₁₋₄ alkylene, (3) —C(O)—, (4) —C(O)—CH₂—, (5) —CH₂—C(O)—, (6) —C(O)O—,or (7) —SO₂— (wherein the bond on the left is bound to the ring2);R² represents (1) a C₁₋₄ alkyl, (2) a C₂₋₄ alkenyl, or (3) a C₂₋₄alkynyl group, each of which may be substituted by from one to fivesubstituents each independently selected from the group consisting of(1) NR³R⁴, (2) halogen atoms, (3) CONR⁵R⁶, (4) CO₂R⁷, and (5) OR⁸;R³ and R⁴ each independently represent (1) a hydrogen atom, or (2) aC₁₋₄ alkyl group which may be substituted by OR⁹ or CONR¹⁰R¹¹; R³ and R⁴may, together with the nitrogen atom to which they are bound, form a 4-to 7-membered nitrogenous saturated heterocycle, which may besubstituted by an oxo group or a hydroxyl group;R⁵ and R⁶ each independently represent (1) a hydrogen atom, (2) a C₁₋₄alkyl group, or (3) a phenyl group;R⁷ represents (1) a hydrogen atom or (2) a C₁₋₄ alkyl group;R⁸ represents (1) a hydrogen atom, (2) a C₁₋₄ alkyl group, (3) a phenylgroup, or (4) a benzotriazolyl group; R⁹ represents (1) a hydrogen atomor (2) a C₁₋₄ alkyl group;R¹⁰ and R¹¹ each independently represent (1) a hydrogen atom or (2) aC₁₋₄ alkyl group;n represents an integer from 0 to 4;m represents an integer from 0 to 2; andwhen n is two or more, the R¹'s may be the same as each other or maydiffer from one another).

In an embodiment, the invention provides the method of any of thepreceding paragraphs, wherein the JAK-2 inhibitor is a compoundaccording to:

or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, wherein:

-   A¹ and A² are independently selected from C and N;-   T, U, and V are independently selected from O, S, N, CR⁵, and NR⁶;-   wherein the 5-membered ring formed by A¹, A², U, T, and V is    aromatic;-   X is N or CR⁴;-   Y is C₁₋₈ alkylene, C₂₋₈ alkenylene, C₂₋₈ alkynylene,    (CR¹¹R¹²)_(p)—(C₃₋₁₀ cycloalkylene)-(CR¹¹R¹²)_(q),    (CR¹¹R¹²)_(p)-(arylene)-(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)—(C₁₋₁₀    heterocycloalkylene)-(CR¹¹R¹²)_(q),    (CR¹¹R¹²)_(p)-(heteroarylene)-(CR¹¹R¹²)_(q),    (CR¹¹R¹²)_(p)O(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)S(CR¹¹R¹²)_(q),    (CR¹¹R¹²)_(p)C(O)(CR¹¹R¹²)_(q),    (CR¹¹R¹²)_(p)C(O)NR^(c)(CR¹¹R¹²)_(q),    (CR¹¹R¹²)_(p)C(O)O(CR¹¹R¹²)_(q), (CR¹¹R¹²)_(p)OC(O)(CR¹¹R¹²)_(q),    (CR¹¹R¹²)_(p)OC(O)NR^(c)(CR¹¹R¹²)_(q),    (CR¹¹R¹²)_(p)NR^(c)(CR¹¹R¹²)_(q),    (CR¹¹R¹²)_(p)NR^(c)C(O)NR^(d)(CR¹¹R¹²)_(q),    (CR¹¹R¹²)_(p)S(O)(CR¹¹R¹²)_(q),    (CR¹¹R¹²)_(p)S(O)NR^(c)(CR¹¹R¹²)_(q),    (CR¹¹R¹²)_(p)S(O)₂(CR¹¹R¹²)_(q), or    (CR¹¹R¹²)_(p)S(O)₂NR^(c)(CR¹¹R¹²)_(q), wherein said C₁₋₈ alkylene,    C₂₋₈ alkenylene, C₂₋₈ alkynylene, cycloalkylene, arylene,    heterocycloalkylene, or heteroarylene, is optionally substituted    with 1, 2, or 3 substituents independently selected from    -D¹-D²-D³-D⁴;-   Z is H, halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄    haloalkyl, halosulfanyl, C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl,    ═C—R^(i), ═N—R^(i), Cy¹, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),    C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),    NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),    NR^(c)C(O)OR^(a), C(═NR^(i))NR^(c)R^(d),    NR^(c)C(═NR^(i))NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),    NR^(c)S(O)₂R^(b), C(═NOH)R^(b), C(═NO(C₁₋₆ alkyl)R^(b), and    S(O)₂NR^(c)R^(d), wherein said C₁₋₈ alkyl, C₂₋₈ alkenyl, or C₂₋₈    alkynyl, is optionally substituted with 1, 2, 3, 4, 5, or 6    substituents independently selected from halo, C₁₋₄ alkyl, C₂₋₄    alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄    hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a),    C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),    OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),    NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), C(═NR^(i))NR^(c)R^(d),    NR^(c)C(═NR^(i))NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),    NR^(c)S(O)₂R^(b), C(═NOH)R^(b), C(═NO(C₁₋₆ alkyl)R^(b), and    S(O)₂NR^(c)R^(d);-   wherein when Z is H, n is 1;-   or the —(Y)_(n)—Z moiety is taken together with i) A² to which the    moiety is attached, ii) R⁵ or R⁶ of either T or V, and iii) the C or    N atom to which the R⁵ or R⁶ of either T or V is attached to form a    4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl    ring fused to the 5-membered ring formed by A¹, A², U, T, and V,    wherein said 4- to 20-membered aryl, cycloalkyl, heteroaryl, or    heterocycloalkyl ring is optionally substituted by 1, 2, 3, 4, or 5    substituents independently selected from -(W)_(m)-Q;-   W is C₁₋₈ alkylenyl, C₂₋₈ alkenylenyl, C₂₋₈ alkynylenyl, O, S, C(O),    C(O)NR^(c′), C(O)O, OC(O), OC(O)NR^(c′), NR^(c′),    NR^(c′)C(O)NR^(d′), S(O), S(O)NR^(c′), S(O)₂, or S(O)₂NR^(c′);-   Q is H, halo, CN, NO₂, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈    haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, or    heterocycloalkyl, wherein said C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈    alkynyl, C₁₋₈ haloalkyl, aryl, cycloalkyl, heteroaryl, or    heterocycloalkyl is optionally substituted with 1, 2, 3 or 4    substituents independently selected from halo, C₁₋₄ alkyl, C₂₋₄    alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄    hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy², CN, NO₂, OR^(a′), SR^(a′),    C(O)R^(b′), C(O)NR^(c′)R^(d′), C(O)OR^(a′), OC(O)R^(b′),    OC(O)NR^(c′)R^(d′), NR^(c′)R^(d′), NR^(c′)C(O)R^(b′),    NR^(c′)C(O)NR^(c′)R^(d′), NR^(c′)C(O)OR^(a′), S(O)R^(b′),    S(O)NR^(c′)R^(d′), S(O)₂R^(b′), NR^(c′)S(O)₂R^(b′), and    S(O)₂NR^(c′)R^(d′);-   Cy¹ and Cy² are independently selected from aryl, heteroaryl,    cycloalkyl, and heterocycloalkyl, each optionally substituted by 1,    2, 3, 4 or 5 substituents independently selected from halo, C₁₋₄    alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, halosulfanyl,    C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, CN, NO₂, OR^(a″), SR^(a″),    C(O)R^(b″), C(O)NR^(c″)R^(d″), C(O)OR^(a″),    OC(O)R^(b″)OC(O)NR^(c″)R^(d″), NR^(c″)R^(d″), NR^(c″)C(O)R^(b″),    NR^(c″)C(O)OR^(a″), NR^(c″)S(O)R^(b″), NR^(c″)S(O)₂R^(b″),    S(O)R^(b″), S(O)NR^(c″)R^(d″), S(O)₂R^(b″), and S(O)₂NR^(c″)R^(d″);-   R¹, R², R³, and R⁴ are independently selected from H, halo, C₁₋₄    alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, halosulfanyl,    aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR⁷, SR⁷,    C(O)R⁸, C(O)NR⁹R¹⁰, C(O)OR⁷OC(O)R⁸, OC(O)NR⁹R¹⁰, NR⁹R¹⁰, NR⁹C(O)R⁸,    NR^(c)C(O)OR⁷, S(O)R⁸, S(O)NR⁹R¹⁰, S(O)₂R⁸, NR⁹S(O)₂R⁸, and    S(O)₂NR⁹R¹⁰;-   R⁵ is H, halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄    haloalkyl, halosulfanyl, CN, NO₂, OR⁷, SR⁷, C(O)R⁸, C(O)NR⁹R¹⁰,    C(O)OR⁷, OC(O)R⁸, OC(O)NR⁹R¹⁰, NR⁹R¹⁰, NR⁹C(O)R⁸, NR⁹C(O)OR⁷,    S(O)R⁸, S(O)NR⁹R¹⁰, S(O)₂R⁸, NR⁹S(O)₂R⁸, or S(O)₂NR⁹R¹⁰;-   R⁶ is H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,    OR⁷, C(O)R⁸, C(O)NR⁹R¹⁰, C(O)OR⁷, S(O)R⁸, S(O)NR⁹R¹⁰, S(O)₂R⁸, or    S(O)₂NR⁹R¹⁰;-   R⁷ is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,    heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl;-   R⁸ is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,    heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl;-   R⁹ and R¹⁰ are independently selected from H, C₁₋₁₀ alkyl, C₁₋₆    haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkylcarbonyl,    arylcarbonyl, C₁₋₆ alkylsulfonyl, arylsulfonyl, aryl, heteroaryl,    cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,    cycloalkylalkyl and heterocycloalkylalkyl;-   or R⁹ and R¹⁰ together with the N atom to which they are attached    form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;-   R¹¹ and R¹² are independently selected from H and -E¹-E²-E³-E⁴;-   D¹ and E¹ are independently absent or independently selected from    C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, arylene,    cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each    of the C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, arylene,    cycloalkylene, heteroarylene, and heterocycloalkylene is optionally    substituted by 1, 2 or 3 substituents independently selected from    halo, CN, NO₂, N₃, SCN, OH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₈    alkoxyalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylamino,    and C₂₋₈ dialkylamino;-   D² and E² are independently absent or independently selected from    C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, (C₁₋₆    alkylene)_(r)-O—(C₁₋₆ alkylene)_(s), (C₁₋₆ alkylene)_(r)-S—(C₁₋₆    alkylene)_(s), (C₁₋₆ alkylene)_(s), —NR^(e)—(C₁₋₆ alkylene)_(s),    (C₁₋₆ alkylene)_(r)-CO—(C₁₋₆ alkylene)_(s), (C₁₋₆    alkylene)_(r)-COO—(C₁₋₆ alkylene)_(s), (C₁₋₆    alkylene)_(r)-CONR^(e)—(C₁₋₆ alkylene)_(s), (C₁₋₆    alkylene)_(r)-SO—(C₁₋₆ alkylene)_(s), (C₁₋₆ alkylene)_(r)-SO₂—(C₁₋₆    alkylene)_(s), (C₁₋₆ alkylene)_(r)-SONR^(e)—(C₁₋₆ alkylene)_(s), and    (C₁₋₆ alkylene)_(r)-NR^(e)CONR^(f)—(C₁₋₆ alkylene)_(s), wherein each    of the C₁₋₆ alkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene is    optionally substituted by 1, 2 or 3 substituents independently    selected from halo, CN, NO₂, N₃, SCN, OH, C₁₋₆ alkyl, C₁₋₆    haloalkyl, C₂₋₈ alkoxyalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino,    C₁₋₆ alkylamino, and C₂₋₈ dialkylamino;-   D³ and E³ are independently absent or independently selected from    C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, arylene,    cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each    of the C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, arylene,    cycloalkylene, heteroarylene, and heterocycloalkylene is optionally    substituted by 1, 2 or 3 substituents independently selected from    halo, CN, NO₂, N₃, SCN, OH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₈    alkoxyalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylamino,    and C₂₋₈ dialkylamino;-   D⁴ and E⁴ are independently selected from H, halo, C₁₋₄ alkyl, C₂₋₄    alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄    hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a),    C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),    OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),    NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), C(═NR^(i))NR^(c)R^(d),    NR^(c)C(═NR^(i))NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),    NR^(c)S(O)₂R^(b), C(═NOH)R^(b), C(═NO(C₁₋₆ alkyl)R^(b), and    S(O)₂NR^(c)R^(d), wherein said C₁₋₈ alkyl, C₂₋₈ alkenyl, or C₂₋₈    alkynyl, is optionally substituted with 1, 2, 3, 4, 5, or 6    substituents independently selected from halo, C₁₋₄ alkyl, C₂₋₄    alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, halosulfanyl, C₁₋₄    hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy¹, CN, NO₂, OR^(a), SR^(a),    C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),    OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),    NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), —C(═NR^(i))NR^(c)R^(d),    NR^(c)C(═NR^(i))NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),    NR^(c)S(O)₂R^(b), C(═NOH)R^(b), C(═NO(C₁₋₆ alkyl))R^(b), and    S(O)₂NR^(c)R^(d);-   R^(a) is H, Cy¹, —(C₁₋₆ alkyl)-Cy¹, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆    alkenyl, or C₂₋₆ alkynyl is optionally substituted with 1, 2, or 3    substituents independently selected from OH, CN, amino, halo, C₁₋₆    alkyl, C₁₋₆ haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl,    heteroarylalkyl, cycloalkyl and heterocycloalkyl;-   R^(b) is H, Cy¹, —(C₁₋₆ alkyl)-Cy¹, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆    alkenyl, or C₂₋₆ alkynyl is optionally substituted with 1, 2, or 3    substituents independently selected from OH, CN, amino, halo, C₁₋₆    alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl, halosulfanyl, aryl,    arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and    heterocycloalkyl;-   R^(a′) and R^(a″) are independently selected from H, C₁₋₆ alkyl,    C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,    heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,    cycloalkylalkyl and heterocycloalkylalkyl, wherein said C₁₋₆ alkyl,    C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,    heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,    cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted    with 1, 2, or 3 substituents independently selected from OH, CN,    amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halosulfanyl, aryl,    arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and    heterocycloalkyl;-   R^(b′) and R^(b″) are independently selected from H, C₁₋₆ alkyl,    C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,    heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,    cycloalkylalkyl and heterocycloalkylalkyl, wherein said C₁₋₆ alkyl,    C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,    heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,    cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted    with 1, 2, or 3 substituents independently selected from OH, CN,    amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl,    halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,    cycloalkyl and heterocycloalkyl;-   R^(c) and R^(d) are independently selected from H, Cy¹, —(C₁₋₆    alkyl)-Cy¹, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, or C₂₋₆    alkynyl, is optionally substituted with 1, 2, or 3 substituents    independently selected from Cy¹, —(C₁₋₆ alkyl)-Cy¹, OH, CN, amino,    halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl, and halosulfanyl;-   or R^(c) and R^(d) together with the N atom to which they are    attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group    optionally substituted with 1, 2, or 3 substituents independently    selected from Cy¹, —(C₁₋₆ alkyl)-Cy¹, OH, CN, amino, halo, C₁₋₆    alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl, and halosulfanyl;-   R^(c′) and R^(d′) are independently selected from H, C₁₋₁₀ alkyl,    C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl,    cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,    cycloalkylalkyl and heterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl,    C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl,    cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,    cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted    with 1, 2, or 3 substituents independently selected from OH, CN,    amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl,    halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,    cycloalkyl and heterocycloalkyl;-   or R^(c′) and R^(d′) together with the N atom to which they are    attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group    optionally substituted with 1, 2, or 3 substituents independently    selected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆    haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl,    heteroarylalkyl, cycloalkyl and heterocycloalkyl;-   R^(c″) and R^(d″) are independently selected from H, C₁₋₁₀ alkyl,    C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl,    cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,    cycloalkylalkyl and heterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl,    C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl,    cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,    cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted    with 1, 2, or 3 substituents independently selected from OH, CN,    amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halosulfanyl, C₁₋₆    haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl    and heterocycloalkyl;-   or R^(c″) and R^(d″) together with the N atom to which they are    attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group    optionally substituted with 1, 2, or 3 substituents independently    selected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆    haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl,    heteroarylalkyl, cycloalkyl and heterocycloalkyl;-   R^(i) is H, CN, NO₂, or C₁₋₆ alkyl;-   R^(e) and R^(f) are independently selected from H and C₁₋₆ alkyl;-   R^(i) is H, CN, or NO₂;-   m is 0 or 1;-   n is 0 or 1;-   p is 0, 1, 2, 3, 4, 5, or 6;-   q is 0, 1, 2, 3, 4, 5 or 6;-   r is 0 or 1; and-   s is 0 or 1.

In an embodiment, the invention provides the method of any of thepreceding paragraphs, wherein the JAK-2 inhibitor is a compoundaccording to:

-   or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal,    or prodrug thereof, wherein:-   R¹ and R² are each independently selected from the group consisting    of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,    heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,    heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl,    heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl,    cycloalkylheteroalkyl, heterocycloalkylheteroalkyl,    heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl,    alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy,    cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy,    benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino,    arylamino, sulfonylamino, sulfinylamino, —COOH, —COR³, —COOR³,    —CONHR³, —NHCOR³, —NHCOOR³, —NHCONHR³, alkoxycarbonyl,    alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl,    arylsulfonyl, arylsulfinyl, aminosulfonyl, —SR³, R⁴S(O)R⁶—,    R⁴S(O)₂R⁶—, R⁴C(O)N(R⁵)R⁶—, R⁴SO₂N(R⁵)R⁶—, R⁴N(R⁵)C(O)R⁶—,    R⁴N(R⁵)SO₂R⁶—, R⁴N(R⁵)C(O)N(R⁵)R⁶— and acyl, each of which may be    optionally substituted;-   each R³, R⁴, and R⁵ is independently selected from the group    consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl,    cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl,    heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of    which may be optionally substituted;-   each R⁶ is independently selected from the group consisting of a    bond, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl,    heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl,    heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of    which may be optionally substituted;-   Z² is independently selected from the group consisting of a bond, O,    S, —N(R⁷)—, —N(R⁷)C₁₋₂ alkyl-, and —C₁₋₂alkylN(R⁷)—;-   each R⁷ is independently selected from the group consisting of H,    alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl,    heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl,    heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of    which may be optionally substituted;-   Ar¹ and Ar² are each independently selected from the group    consisting of aryl and heteroaryl, each of which may be optionally    substituted;-   L is a group of formula:    —X¹—Y—X²—-   wherein X¹ is attached to Ar¹ and X² is attached to Ar², and wherein    X¹, X² and Y are selected such that the group L has between 5 and 15    atoms in the normal chain,-   X¹ and X² are each independently a heteroalkyl group containing at    least one oxygen atom in the normal chain,-   Y is a group of formula —CR^(a)═CR^(b)— or an optionally substituted    cycloalkyl group,-   wherein R^(a) and R^(b) are each independently selected from the    group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl,    heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,    cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl    and acyl, each of which may be optionally substituted, or-   R^(a) and R^(b) may be joined such that when taken together with the    carbon atoms to which they are attached they form a cycloalkenyl or    cycloheteroalkenyl group;-   or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal,    or prodrug thereof, or an N-oxide thereof.-   In certain embodiments Z² is selected from the group consisting of a    bond, —N(R⁷)—, and —S—. In one specific embodiment Z² is —N(R⁷)—. In    an even more specific embodiment Z² is —N(H)—.-   Ar¹ and Ar² are each independently selected from the group    consisting of aryl and heteroaryl and may be monocyclic, bicyclic or    polycyclic moieties. In certain embodiments each of Ar¹ and Ar² is a    monocyclic or bicyclic moiety. In certain embodiments each of Ar¹    and Ar² are a monocyclic moiety.

In certain embodiments Ar¹ is selected from the group consisting of:

-   wherein V¹, V², V³ and V⁴ are each independently selected from the    group consisting of N, and C(R¹⁰);-   W is selected from the group consisting of O, S and NR¹⁰;-   W¹ and W² are each independently selected from the group consisting    of N and CR¹⁰;-   wherein each R¹⁰ is independently selected from the group consisting    of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,    heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,    heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl,    heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl,    cycloalkylheteroalkyl, heterocycloalkylheteroalkyl,    heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl,    alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy,    cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy,    benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino,    arylamino, sulfonylamino, sulfinylamino, —COOH, —COR³, —COOR³,    —CONHR³, —NHCOR³, —NHCOOR³, —NHCONHR³, alkoxycarbonyl,    alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl,    arylsulfonyl, arylsulfinyl, aminosulfonyl, —SR³, R⁴S(O)R⁶—,    R⁴S(O)₂R⁶—, R⁴C(O)N(R⁵)R⁶—, R⁴SO₂N(R⁵)R⁶—, R⁴N(R⁵)C(O)R⁶,    R⁴N(R⁵)SO₂R⁶—, R⁴N(R⁵)C(O)N(R⁵)R⁶— and acyl, each of which may be    optionally substituted,-   wherein R³, R⁴, R⁵ and R⁶ are as defined above.

In certain embodiments Ar¹ is selected from the group consisting of:

-   wherein V¹, V², V³, V⁴, W, W¹, W², R³, R⁴, R⁵ and R⁶ are as defined    above.

In certain embodiments Ar¹ is selected from the group consisting of:

wherein each R¹⁰ is independently as defined above,

-   k is an integer selected from the group consisting of 0, 1, 2, 3,    and 4; and-   n is an integer selected from the group consisting of 0, 1, and 2.

In yet an even further embodiment Ar¹ is selected from the groupconsisting of:

wherein R¹⁰ is as defined above.

In certain embodiments Ar¹ is selected from the group consisting of:

wherein each R¹⁰ is independently as defined above, and

-   q is an integer selected from the group consisting of 0, 1 and 2.

In certain embodiments Ar¹ is selected from the group consisting of:

In certain embodiments Ar¹ is selected from the group consisting of:

In certain embodiments Ar² is selected from the group consisting of:

wherein V⁵, V⁶, V⁷ and V⁸ are independently selected from the groupconsisting of N, and C(R¹¹);wherein each R¹¹ is independently selected from the group consisting of:H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl,heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl,cycloalkylheteroalkyl, heterocycloalkylheteroalkyl,heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy,alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy,heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy,heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino,sulfonylamino, sulfinylamino, —COOH, —COR³, —COOR³, —CONHR³, —NHCOR³,—NHCOOR³, —NHCONHR³, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl,alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl,—SR³, R⁴S(O)R⁶—, R⁴S(O)₂R⁶—, R⁴C(O)N(R⁵)R⁶—, R⁴SO₂N(R⁵)R⁶—,R⁴N(R⁵)C(O)R⁶—, R⁴N(R⁵)SO₂R⁶—, R⁴N(R⁵)C(O)N(R⁵)R⁶— and acyl, each ofwhich may be optionally substituted.

In certain embodiments Ar² is selected from the group consisting of:

wherein each R¹¹ is independently as defined above

-   o is an integer selected from the group consisting of 0, 1, 2, 3,    and 4; and-   p is an integer selected from the group consisting of 0, 1, 2, and    3.

In certain embodiments Ar² is selected from the group consisting of:

wherein each R¹¹ is as defined above.

In an even further embodiment Ar² is selected from the group consistingof:

In an embodiment, the invention provides the method of any of thepreceding paragraphs, wherein the BTK inhibitor is selected from thegroup consisting of:

and pharmaceutically acceptable salts, solvates, hydrates, cocrystals,and prodrugs thereof; and the JAK-2 inhibitor is selected from the groupconsisting of:

and pharmaceutically acceptable salts, solvates, hydrates, cocrystals,and prodrugs thereof.

In an embodiment, the invention provides the method of any of thepreceding paragraphs, wherein the BTK inhibitor is selected from thegroup consisting of:

and pharmaceutically acceptable salts, solvates, hydrates, cocrystals,and prodrugs thereof, and the JAK-2 inhibitor is selected from the groupconsisting of:

and pharmaceutically acceptable salts, solvates, hydrates, cocrystals,and prodrugs thereof; and a PI3K inhibitor selected from the groupconsisting of:

and pharmaceutically acceptable salts, solvates, hydrates, cocrystals,and prodrugs thereof.

In an embodiment, the invention provides a method of treating a solidtumor cancer in a human comprising administering a therapeuticallyeffective amount of a BTK inhibitor, a JAK-2 inhibitor, and/or a PI3K-δinhibitor, wherein the dose is effective to inhibit signaling betweenthe cells of the solid tumor cancer and at least one tumormicroenvironment selected from the group consisting of macrophages,monocytes, mast cells, helper T cells, cytotoxic T cells, regulatory Tcells, natural killer cells, myeloid-derived suppressor cells,regulatory B cells, neutrophils, dendritic cells, and fibroblasts. In anembodiment, the solid tumor cancer is selected from the group consistingof pancreatic cancer, ovarian cancer, colon carcinoma, breast cancer,lung cancer, colorectal cancer, thyroid cancer, bone sarcoma, andstomach cancers. In an embodiment, the invention provides the method ofany of the preceding paragraphs, wherein the dose is further effectiveto increase immune system recognition and rejection of the solid tumorby the human.

Combinations of BTK Inhibitors, PI3K Inhibitors, and/or JAK-2 Inhibitorswith Anti-CD20 Antibodies

The BTK inhibitors of the present invention and combinations of the BTKinhibitors with PI3K inhibitors and/or JAK-2 inhibitors may also besafely co-administered with immunotherapeutic antibodies such as theanti-CD20 antibodies rituximab, obinutuzumab, ofatumumab, veltuzumab,tositumomab, and ibritumomab, and or antigen-binding fragments,derivatives, conjugates, variants, and radioisotope-labeled complexesthereof, which may be given alone or with conventional chemotherapeuticactive pharmaceutical ingredients such as those described herein. In anembodiment, the foregoing combinations exhibit synergistic effects thatmay result in greater efficacy, less side effects, the use of lessactive pharmaceutical ingredient to achieve a given clinical result, orother synergistic effects.

In an embodiment, the invention provides a method of treating ahematological malignancy or a solid tumor cancer in a human comprisingthe step of administering to said human a BTK inhibitor of Formula(XVIII), or a pharmaceutically acceptable salt or ester, prodrug,cocrystal, solvate or hydrate thereof, and further comprising the stepof administering an anti-CD20 antibody, wherein the anti-CD20 antibodyis a monoclonal antibody or an antigen-binding fragment, derivative,conjugate, variant, or radioisotope-labeled complex thereof. In anembodiment, the invention provides a method of treating a hematologicalmalignancy or a solid tumor cancer in a human comprising the step ofadministering to said human a BTK inhibitor of Formula (XVIII), or apharmaceutically acceptable salt or ester, prodrug, cocrystal, solvateor hydrate thereof, and further comprising the step of administering ananti-CD20 antibody, wherein the anti-CD20 antibody is an anti-CD20monoclonal antibody or an antigen-binding fragment, derivative,conjugate, variant, or radioisotope-labeled complex thereof, and whereinthe anti-CD20 antibody specifically binds to human CD20 with a K_(D)selected from the group consisting of 1×10⁻⁷ M or less, 5×10⁻⁸ M orless, 1×10⁻⁸ M or less, and 5×10⁻⁹ M or less. Anti-CD20 monoclonalantibodies are classified as Type I or Type II, as described in Klein,et al., mAbs 2013, 5, 22-33. Type I anti-CD20 monoclonal antibodies arecharacterized by binding to the Class I epitope, localization of CD20 tolipid rafts, high complement-dependent cytotoxicity, full bindingcapacity, weak homotypic aggregation, and moderate cell death induction.Type II anti-CD20 monoclonal antibodies are characterized by binding tothe Class I epitope, a lack of localization of CD20 to lipid rafts, lowcomplement-dependent cytotoxicity, half binding capacity, homotypicaggregation, and strong cell death induction. Both Type I and Type IIanti-CD20 monoclonal antibodies exhibit antibody-dependent cytotoxiticy(ADCC) and are thus useful with BTK inhibitors described herein. Type Ianti-CD20 monoclonal antibodies include but are not limited torituximab, ocrelizumab, and ofatumumab. Type II anti-CD20 monoclonalantibodies include but are not limited to obinutuzumab and tositumomab.In an embodiment, the foregoing methods exhibit synergistic effects thatmay result in greater efficacy, less side effects, the use of lessactive pharmaceutical ingredient to achieve a given clinical result, orother synergistic effects.

In an embodiment, the invention provides a method of treating ahematological malignancy or a solid tumor cancer in a human comprisingthe step of administering to said human a BTK inhibitor of Formula(XVIII), or a pharmaceutically acceptable salt or ester, prodrug,cocrystal, solvate or hydrate thereof, and further comprising the stepof administering an anti-CD20 antibody, wherein the anti-CD20 antibodyis a monoclonal antibody or an antigen-binding fragment, derivative,conjugate, variant, or radioisotope-labeled complex thereof. In anembodiment, the invention provides a method of treating a hematologicalmalignancy or a solid tumor cancer in a human comprising the step ofadministering to said human a BTK inhibitor of Formula (XVIII), or apharmaceutically acceptable salt or ester, prodrug, cocrystal, solvateor hydrate thereof, and further comprising the step of administering ananti-CD20 antibody, wherein the anti-CD20 antibody is an anti-CD20monoclonal antibody or an antigen-binding fragment, derivative,conjugate, variant, or radioisotope-labeled complex thereof, and whereinthe anti-CD20 antibody specifically binds to human CD20 with a K_(D)selected from the group consisting of 1×10⁻⁷ M or less, 5×10⁻⁸ M orless, 1×10⁻⁸ M or less, and 5×10⁻⁹ M or less.

In an embodiment, the invention provides a method of treating ahematological malignancy or a solid tumor cancer in a human comprisingthe step of administering to said human a BTK inhibitor of Formula(XVIII), or a pharmaceutically acceptable salt or ester, prodrug,cocrystal, solvate or hydrate thereof, and further comprising the stepof administering an Type I anti-CD20 antibody, or an antigen-bindingfragment, derivative, conjugate, variant, or radioisotope-labeledcomplex thereof. In an embodiment, the invention provides a method oftreating a hematological malignancy or a solid tumor cancer in a humancomprising the step of administering to said human a BTK inhibitor ofFormula (XVIII), or a pharmaceutically acceptable salt or ester,prodrug, cocrystal, solvate or hydrate thereof, and further comprisingthe step of administering an Type II anti-CD20 antibody, or anantigen-binding fragment, derivative, conjugate, variant, orradioisotope-labeled complex thereof. In an embodiment, the inventionprovides a method of treating a hematological malignancy or a solidtumor cancer in a human comprising the step of administering to saidhuman a BTK inhibitor of Formula (XVIII), or a pharmaceuticallyacceptable salt or ester, prodrug, cocrystal, solvate or hydratethereof, and a JAK-2 inhibitor or a pharmaceutically acceptable salt,solvate, hydrate, cocrystal, or prodrug thereof, and further comprisingthe step of administering an Type I anti-CD20 antibody, or anantigen-binding fragment, derivative, conjugate, variant, orradioisotope-labeled complex thereof. In an embodiment, the inventionprovides a method of treating a hematological malignancy or a solidtumor cancer in a human comprising the step of administering to saidhuman a BTK inhibitor of Formula (XVIII), or a pharmaceuticallyacceptable salt or ester, prodrug, cocrystal, solvate or hydratethereof, and a JAK-2 inhibitor or a pharmaceutically acceptable salt,solvate, hydrate, cocrystal, or prodrug thereof, and further comprisingthe step of administering an Type II anti-CD20 antibody, or anantigen-binding fragment, derivative, conjugate, variant, orradioisotope-labeled complex thereof.

In selected embodiments, the BTK inhibitors of the present invention andcombinations of the BTK inhibitors with PI3K inhibitors, and/or JAK-2inhibitors, and the anti-CD20 monoclonal antibody are administeredsequentially. In selected embodiments, the BTK inhibitors of the presentinvention and combinations of the BTK inhibitors with PI3K inhibitors,and/or JAK-2 inhibitors, and the anti-CD20 monoclonal antibody areadministered concomitantly. In selected embodiments, the BTK inhibitorsof the present invention and combinations of the BTK inhibitors withPI3K inhibitors and/or JAK-2 inhibitors is administered before theanti-CD20 monoclonal antibody. In selected embodiments, the BTKinhibitors of the present invention and combinations of the BTKinhibitors with PI3K inhibitors and/or JAK-2 inhibitors is administeredafter the anticoagulant or the antiplatelet active pharmaceuticalingredient. In selected embodiments, the BTK inhibitors of the presentinvention and combinations of the BTK inhibitors with PI3K inhibitorsand/or JAK-2 inhibitors and the anti-CD20 monoclonal antibody areadministered over the same time period, and the BTK inhibitoradministration continues after the anti-CD20 monoclonal antibodyadministration is completed.

In an embodiment, the anti-CD20 monoclonal antibody is rituximab, or anantigen-binding fragment, derivative, conjugate, variant, orradioisotope-labeled complex thereof. Rituximab is a chimericmurine-human monoclonal antibody directed against CD20, and itsstructure comprises an IgG1 kappa immunoglobulin containing murinelight- and heavy-chain variable region sequences and human constantregion sequences. Rituximab is composed of two heavy chains of 451 aminoacids and two light chains of 213 amino acids. The amino acid sequencefor the heavy chains of rituximab is set forth in SEQ ID NO:1. The aminoacid sequence for the light chains of rituximab is set forth in SEQ IDNO:2. Rituximab is commercially available, and its properties and use incancer and other diseases is described in more detail in Rastetter, etal., Ann. Rev. Med. 2004, 55, 477-503, and in Plosker and Figgett,Drugs, 2003, 63, 803-43. In an embodiment, the anti-CD20 monoclonalantibody is an anti-CD20 biosimilar monoclonal antibody approved by drugregulatory authorities with reference to rituximab. In an embodiment,the anti-CD20 monoclonal antibody has a heavy chain sequence identity ofgreater than 90% to SEQ ID NO:1. In an embodiment, the anti-CD20monoclonal antibody has a light chain sequence identity of greater than90% to SEQ ID NO:2. In an embodiment, the anti-CD20 monoclonal antibodyhas a heavy chain sequence identity of greater than 95% to SEQ ID NO:1.In an embodiment, the anti-CD20 monoclonal antibody has a light chainsequence identity of greater than 95% to SEQ ID NO:2. In an embodiment,the anti-CD20 monoclonal antibody has a heavy chain sequence identity ofgreater than 98% to SEQ ID NO:1. In an embodiment, the anti-CD20monoclonal antibody has a light chain sequence identity of greater than98% to SEQ ID NO:2. In an embodiment, the anti-CD20 monoclonal antibodyhas a heavy chain sequence identity of greater than 99% to SEQ ID NO:1.In an embodiment, the anti-CD20 monoclonal antibody has a light chainsequence identity of greater than 99% to SEQ ID NO:2.

In an embodiment, the anti-CD20 monoclonal antibody is obinutuzumab, oran antigen-binding fragment, derivative, conjugate, variant, orradioisotope-labeled complex thereof. Obinutuzumab is also known asafutuzumab or GA-101. Obinutuzumab is a humanized monoclonal antibodydirected against CD20. The amino acid sequence for the heavy chains ofobinutuzumab is set forth in SEQ ID NO:3. The amino acid sequence forthe light chains of obinutuzumab is set forth in SEQ ID NO:4.Obinutuzumab is commercially available, and its properties and use incancer and other diseases is described in more detail in Robak, Curr.Opin. Investig. Drugs 2009, 10, 588-96. In an embodiment, the anti-CD20monoclonal antibody is an anti-CD20 biosimilar monoclonal antibodyapproved by drug regulatory authorities with reference to obinutuzumab.In an embodiment, the anti-CD20 monoclonal antibody has a heavy chainsequence identity of greater than 90% to SEQ ID NO:3. In an embodiment,the anti-CD20 monoclonal antibody has a light chain sequence identity ofgreater than 90% to SEQ ID NO:4. In an embodiment, the anti-CD20monoclonal antibody has a heavy chain sequence identity of greater than95% to SEQ ID NO:3. In an embodiment, the anti-CD20 monoclonal antibodyhas a light chain sequence identity of greater than 95% to SEQ ID NO:4.In an embodiment, the anti-CD20 monoclonal antibody has a heavy chainsequence identity of greater than 98% to SEQ ID NO:3. In an embodiment,the anti-CD20 monoclonal antibody has a light chain sequence identity ofgreater than 98% to SEQ ID NO:4. In an embodiment, the anti-CD20monoclonal antibody has a heavy chain sequence identity of greater than99% to SEQ ID NO:3. In an embodiment, the anti-CD20 monoclonal antibodyhas a light chain sequence identity of greater than 99% to SEQ ID NO:4.In an embodiment, the anti-CD20 monoclonal antibody obinutuzumab is animmunoglobulin G1, anti-(human B-lymphocyte antigen CD20(membrane-spanning 4-domains subfamily A member 1, B-lymphocyte surfaceantigen B1, Leu-16 or Bp35)), humanized mouse monoclonal obinutuzumabdes-CH3107-K-γ1 heavy chain (222-219′)-disulfide with humanized mousemonoclonal obinutuzumab κ light chain dimer(228-228″:231-231″)-bisdisulfide antibody.

In an embodiment, the anti-CD20 monoclonal antibody is ofatumumab, or anantigen-binding fragment, derivative, conjugate, variant, orradioisotope-labeled complex thereof. Ofatumumab is described in Cheson,J. Clin. Oncol. 2010, 28, 3525-30. The crystal structure of the Fabfragment of ofatumumab has been reported in Protein Data Bank reference3GIZ and in Du, et al., Mol. Immunol. 2009, 46, 2419-2423. Ofatumumab iscommercially available, and its preparation, properties, and use incancer and other diseases are described in more detail in U.S. Pat. No.8,529,202 B2, the disclosure of which is incorporated herein byreference. In an embodiment, the anti-CD20 monoclonal antibody is ananti-CD20 biosimilar monoclonal antibody approved by drug regulatoryauthorities with reference to ofatumumab. In an embodiment, theanti-CD20 monoclonal antibody has a variable heavy chain sequenceidentity of greater than 90% to SEQ ID NO:5. In an embodiment, theanti-CD20 monoclonal antibody has a variable light chain sequenceidentity of greater than 90% to SEQ ID NO:6. In an embodiment, theanti-CD20 monoclonal antibody has a variable heavy chain sequenceidentity of greater than 95% to SEQ ID NO:5. In an embodiment, theanti-CD20 monoclonal antibody has a variable light chain sequenceidentity of greater than 95% to SEQ ID NO:6. In an embodiment, theanti-CD20 monoclonal antibody has a variable heavy chain sequenceidentity of greater than 98% to SEQ ID NO:5. In an embodiment, theanti-CD20 monoclonal antibody has a variable light chain sequenceidentity of greater than 98% to SEQ ID NO:6. In an embodiment, theanti-CD20 monoclonal antibody has a variable heavy chain sequenceidentity of greater than 99% to SEQ ID NO:5. In an embodiment, theanti-CD20 monoclonal antibody has a variable light chain sequenceidentity of greater than 99% to SEQ ID NO:6. In an embodiment, theanti-CD20 monoclonal antibody has a Fab fragment heavy chain sequenceidentity of greater than 90% to SEQ ID NO:7. In an embodiment, theanti-CD20 monoclonal antibody has a Fab fragment light chain sequenceidentity of greater than 90% to SEQ ID NO:8. In an embodiment, theanti-CD20 monoclonal antibody has a Fab fragment heavy chain sequenceidentity of greater than 95% to SEQ ID NO:7. In an embodiment, theanti-CD20 monoclonal antibody has a Fab fragment light chain sequenceidentity of greater than 95% to SEQ ID NO:8. In an embodiment, theanti-CD20 monoclonal antibody has a Fab fragment heavy chain sequenceidentity of greater than 98% to SEQ ID NO:7. In an embodiment, theanti-CD20 monoclonal antibody has a Fab fragment light chain sequenceidentity of greater than 98% to SEQ ID NO:8. In an embodiment, theanti-CD20 monoclonal antibody has a Fab fragment heavy chain sequenceidentity of greater than 99% to SEQ ID NO:7. In an embodiment, theanti-CD20 monoclonal antibody has a Fab fragment light chain sequenceidentity of greater than 99% to SEQ ID NO:8. In an embodiment, theanti-CD20 monoclonal antibody ofatumumab is an immunoglobulin G1,anti-(human B-lymphocyte antigen CD20 (membrane-spanning 4-domainssubfamily A member 1, B-lymphocyte surface antigen B1, Leu-16 or Bp35));human monoclonal ofatumumab-CD20 γ1 heavy chain (225-214′)-disulfidewith human monoclonal ofatumumab-CD20 κ light chain, dimer(231-231″:234-234″)-bisdisulfide antibody.

In an embodiment, the anti-CD20 monoclonal antibody is veltuzumab, or anantigen-binding fragment, derivative, conjugate, variant, orradioisotope-labeled complex thereof. Veltuzumab is also known as hA20.Veltuzumab is described in Goldenberg, et al., Leuk. Lymphoma 2010, 51,747-55. In an embodiment, the anti-CD20 monoclonal antibody is ananti-CD20 biosimilar monoclonal antibody approved by drug regulatoryauthorities with reference to veltuzumab. In an embodiment, theanti-CD20 monoclonal antibody has a heavy chain sequence identity ofgreater than 90% to SEQ ID NO:9. In an embodiment, the anti-CD20monoclonal antibody has a light chain sequence identity of greater than90% to SEQ ID NO:10. In an embodiment, the anti-CD20 monoclonal antibodyhas a heavy chain sequence identity of greater than 95% to SEQ ID NO:9.In an embodiment, the anti-CD20 monoclonal antibody has a light chainsequence identity of greater than 95% to SEQ ID NO:10. In an embodiment,the anti-CD20 monoclonal antibody has a heavy chain sequence identity ofgreater than 98% to SEQ ID NO:9. In an embodiment, the anti-CD20monoclonal antibody has a light chain sequence identity of greater than98% to SEQ ID NO:10. In an embodiment, the anti-CD20 monoclonal antibodyhas a heavy chain sequence identity of greater than 99% to SEQ ID NO:9.In an embodiment, the anti-CD20 monoclonal antibody has a light chainsequence identity of greater than 99% to SEQ ID NO:10. In an embodiment,the anti-CD20 monoclonal antibody ofatumumab is an immunoglobulin G1,anti-(human B-lymphocyte antigen CD20 (membrane-spanning 4-domainssubfamily A member 1, Leu-16, Bp35)); [218-arginine,360-glutamicacid,362-methionine]humanized mouse monoclonal hA20 γ1 heavy chain(224-213′)-disulfide with humanized mouse monoclonal hA20 κ light chain(230-230″:233-233″)-bisdisulfide dimer

In an embodiment, the anti-CD20 monoclonal antibody is tositumomab, oran antigen-binding fragment, derivative, conjugate, variant, orradioisotope-labeled complex thereof. In an embodiment, the anti-CD20monoclonal antibody is ¹³¹I-labeled tositumomab. In an embodiment, theanti-CD20 monoclonal antibody is an anti-CD20 biosimilar monoclonalantibody approved by drug regulatory authorities with reference totositumomab. In an embodiment, the anti-CD20 monoclonal antibody has aheavy chain sequence identity of greater than 90% to SEQ ID NO:11. In anembodiment, the anti-CD20 monoclonal antibody has a light chain sequenceidentity of greater than 90% to SEQ ID NO:12. In an embodiment, theanti-CD20 monoclonal antibody has a heavy chain sequence identity ofgreater than 95% to SEQ ID NO:11. In an embodiment, the anti-CD20monoclonal antibody has a light chain sequence identity of greater than95% to SEQ ID NO:12. In an embodiment, the anti-CD20 monoclonal antibodyhas a heavy chain sequence identity of greater than 98% to SEQ ID NO:11.In an embodiment, the anti-CD20 monoclonal antibody has a light chainsequence identity of greater than 98% to SEQ ID NO:12. In an embodiment,the anti-CD20 monoclonal antibody has a heavy chain sequence identity ofgreater than 99% to SEQ ID NO:11. In an embodiment, the anti-CD20monoclonal antibody has a light chain sequence identity of greater than99% to SEQ ID NO:12.

In an embodiment, the anti-CD20 monoclonal antibody is ibritumomab, oran antigen-binding fragment, derivative, conjugate, variant, orradioisotope-labeled complex thereof. The active form of ibritumomabused in therapy is ibritumomab tiuxetan. When used with ibritumomab, thechelator tiuxetan (diethylene triamine pentaacetic acid) is complexedwith a radioactive isotope such as ⁹⁰Y or ¹¹¹In. In an embodiment, theanti-CD20 monoclonal antibody is ibritumomab tiuxetan, orradioisotope-labeled complex thereof. In an embodiment, the anti-CD20monoclonal antibody is an anti-CD20 biosimilar monoclonal antibodyapproved by drug regulatory authorities with reference to tositumomab.In an embodiment, the anti-CD20 monoclonal antibody has a heavy chainsequence identity of greater than 90% to SEQ ID NO:13. In an embodiment,the anti-CD20 monoclonal antibody has a light chain sequence identity ofgreater than 90% to SEQ ID NO:14. In an embodiment, the anti-CD20monoclonal antibody has a heavy chain sequence identity of greater than95% to SEQ ID NO:13. In an embodiment, the anti-CD20 monoclonal antibodyhas a light chain sequence identity of greater than 95% to SEQ ID NO:14.In an embodiment, the anti-CD20 monoclonal antibody has a heavy chainsequence identity of greater than 98% to SEQ ID NO:13. In an embodiment,the anti-CD20 monoclonal antibody has a light chain sequence identity ofgreater than 98% to SEQ ID NO:14. In an embodiment, the anti-CD20monoclonal antibody has a heavy chain sequence identity of greater than99% to SEQ ID NO:13. In an embodiment, the anti-CD20 monoclonal antibodyhas a light chain sequence identity of greater than 99% to SEQ ID NO:14.

In an embodiment, an anti-CD20 antibody selected from the groupconsisting of obinutuzumab, ofatumumab, veltuzumab, tositumomab, andibritumomab, and or antigen-binding fragments, derivatives, conjugates,variants, and radioisotope-labeled complexes thereof, is administered toa subject by infusing a dose selected from the group consisting of about10 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, 100 mg, about200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg,about 1700 mg, about 1800 mg, about 1900 mg, and about 2000 mg. In anembodiment, the anti-CD20 antibody is admininstered weekly. In anembodiment, the anti-CD20 antibody is admininstered every two weeks. Inan embodiment, the anti-CD20 antibody is admininstered every threeweeks. In an embodiment, the anti-CD20 antibody is admininsteredmonthly. In an embodiment, the anti-CD20 antibody is administered at alower initial dose, which is escalated when administered at subsequentintervals admininstered monthly. For example, the first infusion candeliver 300 mg of anti-CD20 antibody, and subsequent weekly doses coulddeliver 2,000 mg of anti-CD20 antibody for eight weeks, followed bymonthly doses of 2,000 mg of anti-CD20 antibody. During any of theforegoing embodiments, the BTK inhibitors of the present invention andcombinations of the BTK inhibitors with PI3K inhibitors and/or JAK-2inhibitors may be administered daily, twice daily, or at differentintervals as described above, at the dosages described above.

In an embodiment, the invention provides a kit comprising a firstcomposition comprising a BTK inhibitor and/or combinations of the BTKinhibitor with PI3K inhibitor and/or JAK-2 inhibitor and a secondcomposition comprising an anti-CD20 antibody selected from the groupconsisting of rituximab, obinutuzumab, ofatumumab, veltuzumab,tositumomab, and ibritumomab, or an antigen-binding fragment,derivative, conjugate, variant, or radioisotope-labeled complex thereof,for use in the treatment of CLL or SLL, hematological malignancies, Bcell malignancies or, or any of the other diseases described herein. Thecompositions are typically both pharmaceutical compositions. The kit isfor use in co-administration of the anti-CD20 antibody and the BTKinhibitor, either simultaneously or separately, in the treatment of CLLor SLL, hematological malignancies, B cell malignancies, or any of theother diseases described herein.

Combinations of BTK Inhibitors with Chemotherapeutic ActivePharmaceutical Ingredients

The combinations of the BTK inhibitors with PI3K inhibitors and/or JAK-2inhibitors may also be safely co-administered with chemotherapeuticactive pharmaceutical ingredients such as gemcitabine, albumin-boundpaclitaxel (nab-paclitaxel), and bendamustine or bendamustinehydrochloride. In a preferred embodiment, the invention provides amethod of treating a hematological malignancy or a solid tumor cancer ina human comprising the step of administering to said human a BTKinhibitor, a PI3K inhibitor, and/or a JAK-2 inhibitor, and furthercomprising the step of administering a therapeutically-effective amountof gemcitabine, or a pharmaceutically acceptable salt, prodrug,cocrystal, solvate or hydrate thereof. In an embodiment, the inventionprovides a method of treating a hematological malignancy or a solidtumor cancer in a human comprising the step of administering to saidhuman a BTK inhibitor of Formula (XVIII), or a pharmaceuticallyacceptable salt, prodrug, cocrystal, solvate or hydrate thereof, andfurther comprising the step of administering a therapeutically-effectiveamount of gemcitabine, or a pharmaceutically acceptable salt, prodrug,cocrystal, solvate or hydrate thereof. In an embodiment, the solid tumorcancer in any of the foregoing embodiments is pancreatic cancer.

In an embodiment, the invention provides a method of treating ahematological malignancy or a solid tumor cancer in a human comprisingthe step of administering to said human a BTK inhibitor, a PI3Kinhibitor, and/or a JAK-2 inhibitor, and further comprising the step ofadministering a therapeutically-effective amount of albumin-boundpaclitaxel. In an embodiment, the invention provides a method oftreating a hematological malignancy or a solid tumor cancer in a humancomprising the step of administering to said human a BTK inhibitor ofFormula (XVIII), or a pharmaceutically acceptable salt or ester,prodrug, cocrystal, solvate or hydrate thereof, and further comprisingthe step of administering a therapeutically-effective amount ofalbumin-boundpaclitaxel. In an embodiment, the solid tumor cancer in anyof the foregoing embodiments is pancreatic cancer.

In an embodiment, the invention provides a method of treating ahematological malignancy or a solid tumor cancer in a human comprisingthe step of administering to said human a BTK inhibitor, a PI3Kinhibitor, and/or a JAK-2 inhibitor, and further comprising the step ofadministering a therapeutically-effective amount of bendamustinehydrochloride. In an embodiment, the invention provides a method oftreating a hematological malignancy or a solid tumor cancer in a humancomprising the step of administering to said human a BTK inhibitor ofFormula (XVIII), or a pharmaceutically acceptable salt or ester,prodrug, cocrystal, solvate or hydrate thereof, and further comprisingthe step of administering a therapeutically-effective amount ofbendamustine hydrochloride. In an embodiment, the hematologicalmalignancy in any of the foregoing embodiments is CLL or SLL. In anembodiment, the invention provides the treatment of a hematologicalmalignancy, including CLL or SLL, comprising the step of administeringto said human a BTK inhibitor and/or a JAK-2 inhibitor, an anti-CD20antibody selected from the group consisting of rituximab, obinutuzumab,ofatumumab, veltuzumab, tositumomab, ibritumomab, and fragments,derivatives, conjugates, variants, radioisotope-labeled complexes, andbiosimilars thereof, and further comprising the step of administering atherapeutically-effective amount of bendamustine or bendamustinehydrochloride.

The anti-CD20 antibody sequences referenced in the foregoing aresummarized in Table 1.

TABLE 1 Anti-CD20 antibody sequences. IdentifierSequence (One-Letter Amino Acid Symbols) SEQ ID NO: 1QVQLQQPGAE LVKPGASVKM SCKASGYTFT SYNMHWVKQT PGRGLEWIGA IYPGNGDTSY  60NQKFKGKATL TADKSSSTAY MQLSSLTSED SAVYYCARST YYGGDWYFNV WGAGTTVTVS 120AASTKGPSVF PLAPSSKSTS GGTAALGCLV KDYFPEPVTV SWNSGALTSG VHTFPAVLQS 180SGLYSLSSVV TVPSSSLGTQ TYICNVNHKP SNTKVDKKVE PKSCDKTHTC PPCPAPELLG 240GPSVFLFPPK PKDTLMISRT PEVTCVVVDV SHEDPEVKFN WYVDGVEVHN AKTKPREEQY 300NSTYRVVSVL TVLHQDWLNG KEYKCKVSNK ALPAPIEKTI SKAKGQPREP QVYTLPPSRD 360ELTKNQVSLT CLVKGFYPSD IAVEWESNGQ PENNYKTTPP VLDSDGSFFL YSKLTVDKSR 420WQQGNVFSCS VMHEALHNHY TQKSLSLSPG K 451 SEQ ID NO: 2QIVLSQSPAI LSASPGEKVT MTCRASSSVS YIHWFQQKPG SSPKPWIYAT SNLASGVPVR  60FSGSGSGTSY SLTISRVEAE DAATYYCQQW TSNPPTFGGG TKLEIKRTVA APSVFIFPPS 120DEQLKSGTAS VVCLLNNFYP REAKVQWKVD NALQSGNSQE SVTEQDSKDS TYSLSSTLTL 180SKADYEKHKV YACEVTHQGL SSPVTKSFNR GEC 213 SEQ ID NO: 3QVQLVQSGAE VKKPGSSVKV SCKASGYAFS YSWINWVRQA PGQGLEWMGR IFPGDGDTDY  60NGKFKGRVTI TADKSTSTAY MELSSLRSED TAVYYCARNV FDGYWLVYWG QGTLVTVSSA 120STKGPSVFPL APSSKSTSGG TAALGCLVKD YFPEPVTVSW NSGALTSGVH TFPAVLQSSG 180LYSLSSVVTV PSSSLGTQTY ICNVNHKPSN TKVDKKVEPK SCDKTHTCPP CPAPELLGGP 240SVFLFPPKPK DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS 300TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV YTLPPSRDEL 360TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL DSDGSFFLYS KLTVDKSRWQ 420QGNVFSCSVM HEALHNHYTQ KSLSLSPGK 449 SEQ ID NO: 4DIVMTQTPLS LPVTPGEPAS ISCRSSKSLL HSNGITYLYW YLQKPGQSPQ LLIYQMSNLV  60SGVPDRFSGS GSGTDFTLKI SRVEAEDVGV YYCAQNLELP YTFGGGTKVE IKRTVAAPSV 120FIFPPSDEQL KSGTASVVCL LNNFYPREAK VQWKVDNALQ SGNSQESVTE QDSKDSTYSL 180SSTLTLSKAD YEKHKVYACE VTHQGLSSPV TKSFNRGEC 219 SEQ ID NO: 5EVQLVESGGG LVQPGRSLRL SCAASGFTFN DYAMHWVRQA PGKGLEWVST ISWNSGSIGY  60ADSVKGRFTI SRDNAKKSLY LQMNSLRAED TALYYCAKDI QYGNYYYGMD VWGQGTTVTV 120 SS122 SEQ ID NO: 6EIVLTQSPAT LSTSPGERAT LSCRASQSVS SYLAWYQQKP GQAPRLLIYD ASNRATGIPA  60RFSGSGSGTD FTLTISSLEP EDFAVYYCQQ RSNWPITFGQ GTRLEIK 107 SEQ ID NO: 7EVQLVESGGG LVQPGRSLRL SCAASGFTFN DYAMHWVRQA PGKGLEWVST ISWNSGSIGY  60ADSVKGRFTI SRDNAKKSLY LQMNSLRAED TALYYCAKDI QYGNYYYGMD VWGQGTTVTV 120SSASTKGPSV FPLAPGSSKS TSGTAALGCL VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ 180SSGLYSLSSV VTVPSSSLGT QTYICNVNHK PSNTKVDKKV EP 222 SEQ ID NO: 8EIVLTQSPAT LSLSPGERAT LSCRASQSVS SYLAWYQQKP GQAPRLLIYD ASNRATGIPA  60RFSGSGSGTD FTLTISSLEP EDFAVYYCQQ RSNWPITFGQ GTRLEIKRTV AAPSVFIFPP 120SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT 180LSKADYEKHK VYACEVTHQG LSSPVTKSFN R 211 SEQ ID NO: 9QVQLQQSGAE VKKPGSSVKV SCKASGYTFT SYNMHWVKQA PGQGLEWIGA IYPGMGDTSY  60NQKFKGKATL TADESTNTAY MELSSLRSED TAFYYCARST YYGGDWYFDV WGQGTTVTVS 120SASTKGPSVF PLAPSSKSTS GGTAALGCLV KDYFPEPVTV SWNSGALTSG VHTFPAVLQS 180SGLYSLSSVV TVPSSSLGTQ TYICNVNHKP SNTKVDKRVE PKSCDKTHTC PPCPAPELLG 240GPSVFLFPPK PKDTLMISRT PEVTCVVVDV SHEDPEVKFN WYVDGVEVHN AKTKPREEQY 300NSTYRVVSVL TVLHQDWLNG KEYKCKVSNK ALPAPIEKTI SKAKGQPREP QVYTLPPSRE 360EMTKNQVSLT CLVKGFYPSD IAVEWESNGQ PENNYKTTPP VLDSDGSFFL YSKLTVDKSR 420WQQGNVFSCS VMHEALHNHY TQKSLSLSPG K 451 SEQ ID NO: 10DIQLTQSPSS LSASVGDRVT MTCRASSSVS YIHWFQQKPG KAPKPWIYAT SNLASGVPVR  60FSGSGSGTDY TFTISSLQPE DIATYYCQQW TSNPPTFGGG TKLEIKRTVA APSVFIFPPS 120DEQLKSGTAS VVCLLNNFYP REAKVQWKVD NALQSGNSQE SVTEQDSKDS TYSLSSTLTL 180SKADYEKHKV YACEVTHQGL SSPVTKSFNR GEC 213 SEQ ID NO: 11QAYLQQSGAE LVRPGASVKM SCKASGYTFT SYNMHWVKQT PRQGLEWIGA IYPGNGDTSY  60NQKFKGKATL TVDKSSSTAY MQLSSLTSED SAVYFCARVV YYSNSYWYFD VWGTGTTVTV 120SGPSVFPLAP SSKSTSGGTA ALGCLVKDYF PEPVTVSWNS GALTSGVHTF PAVLQSSGLY 180SLSSVVTVPS SSLGTQTYIC NVNHKPSNTK VDKKAEPKSC DKTHTCPPCP APELLGGPSV 240FLFPPKPKDT LMISRTPEVT CVVVDVSHED PEVKFNWYVD GVEVHNAKTK PREEQYNSTY 300RVVSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK GQPREPQVYT LPPSRDELTK 360NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSKL TVDKSRWQQG 420NVFSCSVMHE ALHNHYTQKS LSLSPGK 447 SEQ ID NO: 12QIVLSQSPAI LSASPGEKVT MTCRASSSVS YMHWYQQKPG SSPKPWIYAP SNLASGVPAR  60FSGSGSGTSY SLTISRVEAE DAATYYCQQW SFNPPTFGAG TKLELKRTVA APSVFIFPPS 120DEQLKSGTAS VVCLLNNFYP REAKVQWKVD NALQSGNSQE SVTEQDSKDS TYSLSSTLTL 180SKADYEKHKV YACEVTHQGL SSPVTKSFNR 210 SEQ ID NO: 13QAYLQQSGAE LVRPGASVKM SCKASGYTFT SYNMHWVKQT PRQGLEWIGA IYPGNGDTSY  60NQKFKGKATL TVDKSSSTAY MQLSSLTSED SAVYFCARVV YYSNSYWYFD VWGTGTTVTV 120SAPSVYPLAP VCGDTTGSSV TLGCLVKGYF PEPVTLTWNS GSLSSGVHTF PAVLQSDLYT 180LSSSVTVTSS TWPSQSITCN VAHPASSTKV DKKIEPRGPT IKPCPPCKCP APNLLGGPSV 240FIFPPKIKDV LMISLSPIVT CVVVDVSEDD PDVQISWFVN NVEVHTAQTQ THREDYNSTL 300RVVSALPIQH QDWMSGKEFK CKVNNKDLPA PIERTISKPK GSVRAPQVYV LPPPEEEMTK 360KQVILICMVT DFMPEDIYVE WTNNGKTELN YKNTEPVLDS DGSYFMYSKL RVEKKNWVER 420NSYSCSVVHE GLHNHHTTKS FSR 443 SEQ ID NO: 14QIVLSQSPAI LSASPGEKVT MTCRASSSVS YMHWYQQKPG SSPKPWIYAP SNLASGVPAR  60FSGSGSGTSY SLTISRVEAE DAATYYCQQW SFNPPTFGAG TKLELKRADA APTVFIFPPS 120DEQLKSGTAS VVCLLNNFYP REAKVQWKVD NALQSGNSQE SVTEQDSKDS TYSLSSTLTL 180SKADYEKHKV YACEVTHQGL SSPVTKSFN 209

While preferred embodiments of the invention are shown and describedherein, such embodiments are provided by way of example only and are notintended to otherwise limit the scope of the invention. Variousalternatives to the described embodiments of the invention may beemployed in practicing the invention.

EXAMPLES

The embodiments encompassed herein are now described with reference tothe following examples. These examples are provided for the purpose ofillustration only and the disclosure encompassed herein should in no waybe construed as being limited to these examples, but rather should beconstrued to encompass any and all variations which become evident as aresult of the teachings provided herein.

Example 1—Synergistic Combination of a BTK Inhibitor and a PI3K-δInhibitor

Ficoll purified mantle cell lymphoma (MCL) cells (2×10⁵) isolated frombone marrow or peripheral blood were treated with each drug alone andwith six equimolar concentrations of a BTK inhibitor (Formula (XVIII))and a PI3K-δ inhibitor (Formula (IX)) ranging from 0.01 nM to 10 μM on96-well plates in triplicate. Plated cells were then cultured in HS-5conditioned media at 37° C. with 5% CO₂. After 72 hours of culture, cellviability was determined using an(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium)(MTS) assay (Cell Titer 96, Promega). Viability data were used togenerate cell viability curves for each drug alone and in combinationfor each sample. The potential synergy of the combination of the BTKinhibitor of Formula (XVIII) and the PI3K-δ inhibitor of Formula (IX) ata given equimolar concentration was determined using the median effectmodel as described in Chou and Talalay, Adv Enzyme Regul. 1984, 22,27-55. The statistical modeling was run in R using a script thatutilizes the median effect model as described in Lee et al., J.Biopharm. Slat. 2007, 17, 461-80. A value of 1, less than 1, and greaterthan 1 using R defines an additive interaction, a synergisticinteraction, and an antagonistic interaction, respectively. The Lee etal. method calculates a 95% confidence interval for each data point. Foreach viability curve, to be considered synergistic, a data point musthave an interaction index below 1 and the upper confidence interval mustalso be below 1. In order to summarize and demonstrate collectivesynergy results, an interaction dot blot was generated for the primarypatient samples.

A similar approach was utilized to study diffuse large B cell lymphoma(DLBCL) (TMD8) and MCL (MINO) cell lines. Cells were treated with eachdrug alone and with six equimolar concentrations of the BTK inhibitor ofFormula (XVIII) and the PI3K-δ inhibitor of Formula (IX) ranging from0.003 nM to 1.0 μM (for TMD8) or 0.03 nM to 10 μM (for MINO) on 96-wellplates in triplicate. Plated cells were then cultured in standardconditioned media plus FBS at 37° C. with 5% CO₂. After 72 hours ofculture, viability was determined using an MTS assay (Cell Titer 96,Promega). Viability data were used to generate cell viability curves foreach drug alone and in combination for each sample. The results of theexperiments described in this example are shown in FIG. 1, FIG. 2, FIG.3, and FIG. 4.

Example 2—Synergistic Combination of a BTK Inhibitor and a PI3K-δInhibitor

Combination experiments were performed to determine the synergistic,additive, or antagonistic behavior of drug combinations using theChou/Talalay method/algorithm by defining combination indexes for drugcombinations. Information about experimental design for evaluation ofsynergy is described in e.g. Chou and Talalay, Adv. Enzyme Regul. 1984,22, 27-55 and more generally in e.g. Greco et al., Pharmacol. Rev. 1995,47, 331-385. The study was performed using the BTK inhibitor of Formula(XVIII) and the PI3K-δ inhibitor of Formula (IX). Single drug activitieswere first determined in the various cell lines and subsequently, thecombination indexes were established using equimolar ratios taking thesingle agent drug EC50s into consideration. For individual drugs thatdisplayed no single drug activity, equimolar ratios were used at fixedconcentrations to establish combination indexes. The readout from 72hour proliferation assays using Cell TiterGlo (ATP content of remainingcells) determined the fraction of cells that were effected as comparedto untreated cells (Fa=fractionaffected=(1−((cells+inhibitor)−backgroundsignal)/((cells+DMSO)−background signal)).

The combination index obtained was ranked according to Table 2.

TABLE 2 Combination Index (CI) Ranking Scheme Range of CI Description<0.1 Very strong synergism 0.1-0.3 Strong synergism 0.3-0.7 Synergism 0.7-0.85 Moderate synergism 0.85-0.9  Slight synergism 0.9-1.1 Nearlyadditive 1.1-1.2 Slight antagonism  1.2-1.45 Moderate antagonism1.45-3.3  Antagonism 3.3-10  Strong antagonism >10 Very strongantagonism

The detailed results of the cell line studies for the BTK inhibitor ofFormula (XVIII) and the PI3K-δ inhibitor of Formula (IX) are given inFIG. 5 to FIG. 37. The results of the cell line studies are summarizedin Table 3.

TABLE 3 Summary of results of the combination of a BTK inhibitor with aPI3K-δ inhibitor (S = synergistic, A = additive, X = no effect). CellLine Indication ED25 ED50 ED75 ED90 Raji Burkitt's S S S S RamosBurkitt's X X X X Daudi Burkitt's S S S S Mino MCL S S S S Pfeiffer iNHLS S S S DOHH iNHL S S S S REC-1 iNHL S S A A U937 Myeloid S S S S K562CML X X X X SU-DHL-1 ABC S A X X SU-DHL-2 ABC S S S S HBL-1 ABC S S S STMD8 ABC S S S S LY19 GCB X X X X LY7 GCB S S S S LY1 GCB X X X XSU-DHL-6 GCB S S S S SupB15 B-ALL S S S S CCRF B-ALL S A/S X X

Example 3—Synergistic Combination of a BTK Inhibitor and the JAK-2Inhibitor Ruxolitinib

Combination experiments were performed to determine the synergistic,additive, or antagonistic behavior of drug combinations using themethods described above in Example 2. The study was performed using theBTK inhibitor of Formula (XVIII) and the JAK-2 inhibitor of Formula XXX(ruxolitinib).

The detailed results of the cell line studies for the BTK inhibitor ofFormula (XVIII) and the JAK-2 inhibitor of Formula XXX (ruxolitinib) aregiven in FIG. 38 to FIG. 65. The results of the cell line studies aresummarized in Table 4.

TABLE 4 Summary of results of the combination of a BTK inhibitor withthe JAK-2 inhibitor of Formula XXX (ruxolitinib) (S = synergistic, A =additive, X = no effect). Cell Line Indication ED25 ED50 ED75 ED90 RajiBurkitt's S S S S Ramos Burkitt's S S S S Daudi Burkitt's S S S S MinoMCL S S S S Pfeiffer iNHL S S S S DOHH iNHL S S S S REC-1 iNHL S S S SJVM-2 CLL like S S S X U937 Myeloid X X X X K562 CML X X X X SU-DHL-1ABC S S S S SU-DHL-2 ABC S S S X HBL-1 ABC S S S S TMD8 ABC S S S S LY19GCB X X X X LY7 GCB X X X X LY1 GCB X X X X SU-DHL-6 GCB S S X X SupB15B-ALL X X X X CCRF B-ALL X X A A

Example 4—Synergistic Combination of a BTK Inhibitor and the JAK-2Inhibitor Pacritinib

Combination experiments were performed to determine the synergistic,additive, or antagonistic behavior of drug combinations using themethods described above in Example 2. The study was performed using theBTK inhibitor of Formula (XVIII) and the JAK-2 inhibitor of Formula LIV(pacritinib).

The detailed results of the cell line studies for the BTK inhibitor ofFormula (XVIII) and the JAK-2 inhibitor of Formula LIV (pacritinib) aregiven in FIG. 66 to FIG. 94. The results of the cell line studies aresummarized in Table 5.

TABLE 5 Summary of results of the combination of a BTK inhibitor withthe JAK-2 inhibitor of Formula LIV (pacritinib) (S = synergistic, A =additive, X = no effect). Cell Line Indication ED25 ED50 ED75 ED90 MinoMCL S S S S JVM-2 prolymphocytic leukemia S S S S Maver-1 B-ALL, MCL S SS S Raji B-ALL, Burkitt's S S S S Daudi Burkitt's S S S S Rec-1 FL X S SS CCRF B-ALL S S S S Sup-B15 B-ALL S S A A SU-DHL-4 DLBCL-ABC S S S SEB3 B-ALL, Burkitt's S S S S CA46 B-ALL, Burkitt's S S S S Pfeiffer FL SS S S DB B-ALL, MCL S S S S DOHH2 FL S S S S Namalwa B-ALL, Burkitt's SS S S JVM-13 B-ALL, MCL S S S S SU-DHL-1 DLBCL-ABC S S S S SU-DHL-2DLBCL-ABC S S S X Ramos Burkitt's S S S S SU-DHL-6 DLBCL-GCB S S S ATMD-8 DLBCL-ABC X X S S SU-DHL-10 DLBCL-GCB S S S S HBL-1 DLBCL-ABC S SS X OCI-Ly3 DLBCL-ABC S S S S OCI-Ly7 DLBCL-ABC S S S S Jeko B-ALL, MCLS S S S

Example 5—Effects of BTK Inhibitors on Thrombosis

Clinical studies have shown that targeting the BCR signaling pathway byinhibiting BTK produces significant clinical benefit (Byrd, et al., N.Engl. J. Med. 2013, 369(1), 32-42, Wang, et al., N. Engl. J. Med. 2013,369(6), 507-16). However, in these studies, bleeding has been reportedin up to 50% of ibrutinib-treated patients. Most bleeding events were ofgrade 1-2 (spontaneous bruising or petechiae) but, in 5% of patients,they were of grade 3 or higher after trauma. These results are reflectedin the prescribing information for ibrutinib, where bleeding events ofany grade, including bruising and petechiae, were reported in about halfof patients treated with ibrutinib (IMBRUVICA package insert andprescribing information, revised July 2014, U.S. Food and DrugAdministration).

Constitutive or aberrant activation of the BCR signaling cascade hasbeen implicated in the propagation and maintenance of a variety of Bcell malignancies. Small molecule inhibitors of BTK, a protein early inthis cascade and specifically expressed in B cells, have emerged as anew class of targeted agents. There are several BTK inhibitors,including Formula XXVII (CC-292), and Formula XX-A (PCI-32765,ibrutinib), in clinical development. Importantly, early stage clinicaltrials have found ibrutinib to be particularly active in chroniclymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), suggestingthat this class of inhibitors may play a significant role in varioustypes of cancers (Aalipour and Advani, Br. J. Haematol. 2013, 163,436-43). However, their effects are not limited to leukemia or lymphomasas platelets also rely on the Tec kinases family members BTK and Tec forsignal transduction in response to various thrombogenic stimuli (Oda, etal., Blood 2000, 95(5), 1663-70; Atkinson, et al., Blood 2003, 102(10),3592-99). In fact, both Tec and BTK play an important role in theregulation of phospholipase Cγ2 (PLCγ2) downstream of the collagenreceptor glycoprotein VI (GPVI) in human platelets. In addition, BTK isactivated and undergoes tyrosine phosphorylation upon challenge of theplatelet thrombin receptor, which requires the engagement of αIIbβ3integrin and PI3K activity (Laffargue, et al., FEBS Lett. 1999, 443(1),66-70). It has also been implicated in GPIbα-dependent thrombusstability at sites of vascular injury (Liu, et al., Blood 2006, 108(8),2596-603). Thus, BTK and Tec are involved in several processes importantin supporting the formation of a stable hemostatic plug, which iscritical for preventing significant blood loss in response to vascularinjury. Hence, the effects of the BTK inhibitor of Formula (XVIII) andibrutinib were evaluated on human platelet-mediated thrombosis byutilizing the in vivo human thrombus formation in the VWF HA1 mice modeldescribed in Chen, et al., Nat. Biotechnol. 2008, 26(1), 114-19.

Administration of anesthesia, insertion of venous and arterialcatheters, fluorescent labeling and administration of human platelets(5×10⁸/ml), and surgical preparation of the cremaster muscle in micehave been previously described (Chen et al., Nat Biotechnol. 2008,26(1), 114-19). Injury to the vessel wall of arterioles (˜40-65 mmdiameter) was performed using a pulsed nitrogen dye laser (440 nm,Photonic Instruments) applied through a 20× water-immersion Olympusobjective (LUMPlanFI, 0.5 numerical aperature (NA)) of a Zeiss Axiotechvario microscope. Human platelet and wall interactions were visualizedby fluorescence microscopy using a system equipped with a YokogawaCSU-22 spinning disk confocal scanner, iXON EM camera, and 488 nm and561 nm laser lines to detect BCECF-labeled and rhodamine-labeledplatelets, respectively (Revolution XD, Andor Technology). The extent ofthrombus formation was assessed for 2 minutes after injury and the area(μm²) of coverage determined (Image IQ, Andor Technology). For theFormula (XVIII), Formula (XXVII) (CC-292), and Formula (XX-A)(ibrutinib) inhibition studies, the BTK inhibitors were added topurified human platelets for 30 minutes before administration.

The in vivo throbus effects of the BTK inhibitors, Formula (XVIII),Formula (XXVII) (CC-292), and Formula (XX-A) (ibrutinib), were evaluatedon human platelet-mediated thrombosis by utilizing the in vivo humanthrombus formation in the VWF HA1 mice model, which has been previouslydescribed (Chen, et al., Nat Biotechnol. 2008, 26(1), 114-19). Purifiedhuman platelets were preincubated with various concentrations of the BTKinhibitors (0.1 μM, 0.5 μM, or 1 μM) or DMSO and then administered toVWF HA1 mice, followed by laser-induced thrombus formation. The BTKinhibitor-treated human platelets were fluorescently labeled and infusedcontinuously through a catheter inserted into the femoral artery. Theirbehavior in response to laser-induced vascular injury was monitored inreal time using two-channel confocal intravital microscopy (Furie andFurie, J. Clin. Invest. 2005, 115(12), 2255-62). Upon induction ofarteriole injury untreated platelets rapidly formed thrombi with anaverage thrombus size of 6,450±292 mm² (mean±s.e.m.), as shown in FIG.95.

The objective of this study was to evaluate in vivo thrombus formationin the presence of BTK inhibitors. In vivo testing of novel antiplateletagents requires informative biomarkers. By utilizing a genetic modifiedmouse von Willebrand factor (VWFR1326H) model that supports human butnot mouse platelet-mediated thrombosis, we evaluated the effects ofFormula (XVIII), Formula XXVII (CC-292), and Formula XX-A (ibrutinib) onthrombus formation. These results show that Formula (XVIII) had nosignificant effect on human platelet-mediated thrombus formation whileFormula XX-A (ibrutinib) was able to limit this process, resulting in areduction in maximal thrombus size by 61% compared with control. FormulaXXVII (CC-292) showed an effect similar to Formula XX-A (ibrutinib).These results, which show reduced thrombus formation for ibrutinib atphysiologically relevant concentrations, may provide some mechanisticbackground for the Grade ≥3 bleeding events (eg, subdural hematoma,gastrointestinal bleeding, hematuria and postprocedural hemorrhage) thathave been reported in ≤6% of patients treated with Formula XX-A(ibrutinib).

GPVI platelet aggregation was measured for Formula (XVIII) and FormulaXX-A (ibrutinib). Blood was obtained from untreated humans, andplatelets were purified from plasma-rich protein by centrifugation.Cells were resuspended to a final concentration of 350,000/μL in buffercontaining 145 mmol/L NaCl, 10 mmol/L HEPES, 0.5 mmol/L Na₂HPO₄, 5mmol/L KCl, 2 mmol/L MgCl₂, 1 mmol/L CaCl₂, and 0.1% glucose, at pH 7.4.Stock solutions of Convulxin (CVX) GPVI were prepared on the day ofexperimentation and added to platelet suspensions 5 minutes (37° C.,1200 rpm) before the induction of aggregation. Aggregation was assessedwith a Chronolog Lumi-Aggregometer (model 540 VS; Chronolog, Havertown,Pa.) and permitted to proceed for 6 minutes after the addition ofagonist. The results are reported as maximum percent change in lighttransmittance from baseline with platelet buffer used as a reference.The results are shown in FIG. 96.

In FIG. 97, the results of CVX-induced (250 ng/mL) human plateletaggregation results before and 15 minutes after administration of theBTK inhibitors to 6 healthy individuals are shown.

The results depicted in FIG. 96 and FIG. 97 indicate that the BTKinhibitor of Formula XX-A (ibrutinib) significantly inhibits GPVIplatelet aggregation, while the BTK inhibitor of Formula (XVIII) doesnot, further illustrating the surprising benefits of the lattercompound. Furthermore, the combination of the BTK inhibitor of Formula(XVIII) with a JAK-2 inhibitor, including the JAK-2 inhibitorsruxolitinib and pacritinib, is suprisingly favorable because of thetendency of these JAK-2 inhibitors to cause thrombocytopenia and otherdisordered associated with increased bleeding.

Example 6—Study of a BTK Inhibitor and a Combination of a BTK Inhibitorand a PI3K Inhibitor in Canine Lymphoma

Canine B cell lymphoma exists as a pathological entity that ischaracterized by large anaplastic, centroblastic or immunoblasticlymphocytes with high proliferative grade, significant peripherallymphadenopathy and an aggressive clinical course. While some dogsrespond initially to prednisone, most canine lymphomas progress quicklyand must be treated with combination therapies, includingcyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP), orother cytotoxic agents. In their histopathologic features, clinicalcourse, and high relapse rate after initial treatment, canine B celllymphomas resemble diffuse large B cell lymphoma (DLBCL) in humans.Thus, responses of canine B cell lymphomas to experimental treatmentsare considered to provide proof of concept for therapeutic candidates inDLBCL.

In this example, companion dogs with newly diagnosed orrelapsed/refractory B cell lymphoma were enrolled on a veterinaryclinical trial of the BTK inhibitor of Formula (XVIII) (“Arm 1”) or theBTK inhibitor of Formula (XVIII) and the PI3K-δ inhibitor of Formula(IX) (“Arm 2”). Enrollment has completed for both arms. The results showthat combined treatment with the BTK inhibitor of Formula (XVIII) andthe PI3K-δ inhibitor of Formula (IX) may have greater efficacy thantreatment with the BTK inhibitor of Formula (XVIII) alone in aggressivelymphomas.

Twenty-one dogs were treated in Arm 1 with the BTK inhibitor of Formula(XVIII) at dosages of 2.5 mg/kg once daily to 20 mg/kg twice daily.Intra-subject dose escalation was allowed. Six of the 11 dogs thatinitiated at 2.5 or 5 mg/kg once daily were escalated and completed thestudy with dosages of 10 mg/kg twice daily. Among all the dose cohorts,8 dogs had shrinkage of target lesions >20%; the best tumor responseswere between 45-49% reduction in the sum of target lesions in two dogs.Complete responses (“CR”, disappearance of all evidence of disease perevaluator judgment; and absence of new lesions) were not observed inArm 1. CR were defined as disappearance of all evidence of disease perevaluator judgment, and absence of new lesions. Vali, et al., Vet. Comp.Oncol. 2010, 8, 28-37.

In the combination phase of the study (Arm 2), 10 dogs were treated with10 mg/kg the BTK inhibitor of Formula (XVIII) and the PI3K-δ inhibitorof Formula (IX) at 2.5 or 3.5 mg/kg, on a twice daily schedule. Ofthese, 7 dogs had shrinkage of target lesions >20%, providing evidenceof biological activity for the combination; four of these dogs achieveda PR. The best tumor responses were between 58-65% reduction in the sumof target lesions, with one sustained CR observed among the 10 dogstreated. The initial reductions in the sum of target lesions continuedto deepen during the course of therapy in 7 of the 10 dogs. A summary ofthe results is presented in Table 6.

TABLE 6 Summary of the results of the canine lymphoma study. Formula(XVIII) and Formula (XVIII) Response Metric Formula (IX) monotherapy SumLD^(a) decreased by ≥20% 7/10 (70%) 8/21 (38%) Sum LD^(a) decreased by≥30% (PR) 4/10 (40%) 6/21 (28.6%) CR by investigator evaluation 1/10(10%) 0/21 (0%) Median time on study 23 days 24 days Median time to bestresponse 18 days  7 days ^(a)LD, longest diameter, sum of up to 5 targetlesions.

These data suggest that in companion dogs with naturally occurring Bcell lymphomas, treatment with the combination of the BTK inhibitor ofFormula (XVIII) and the PI3K-δ inhibitor of Formula (IX) may provideincreased biological activity (tumor shrinkage and stable disease) andmay possibly lead to deeper responses than treatment with the BTKinhibitor of Formula (XVIII) alone. The higher rate of biologicalresponses and extended response duration (median time to best response),along with the observation of a CR in this aggressive disease setting,provide evidence of synergy between Formula (XVIII) and Formula (IX).

Example 7—Study of a Combination of a BTK Inhibitor and a PI3K Inhibitorin DLBCL Cell Lines

To explore the role of PI3K signaling in diffuse large B-cell lymphoma(“DLBCL”), several DLBCL cell lines of varying molecular profiles may beutilized. In an exemplary embodiment, a cellular growth inhibition assayused five cell lines, including four GCB (SU-DHL-4, SU-DHL-6, OCI-LY-8and WSU-DLCL-2) and one ABC (Ri-1) subtype. In an exemplary embodiment,a cellular growth inhibition assay used five cell lines that wereOCI-LY-3, OCI-LY-7, Pfeiffer, Toledo and U2932. In an exemplaryembodiment, evidence of PI3K pathway inhibition is measured by reductionin phospho (p)-AKT. In an exemplary embodiment, the kinetics of pathwaymodulation was characterized by examination of phosphorylation of AKT,PRAS40 and S6 following a time-course of treatment by a PI3K-inhibitorin selected cell lines. In one embodiment, upon B-cell receptorstimulation via antibody-induced crosslinking, some cell lines exhibitedenhanced AKT phosphorylation.

In an exemplary embodiment, the combination effect of a PI3K inhibitorwith a BTK inhibitor was observed in a cellular growth inhibition assayin the SU-DHL-4 cell line and in the OCI-LY-8 cell line with BCRcrosslinking.

Example 8—Effects of BTK Inhibition on Antibody-Dependent NK CellMediated Cytotoxicity Using Obinutuzumab

It has been shown above that ibrutinib undesirably antagonizes rituximabADCC effects mediated by NK cells, and that Formula (XVIII) does notantagonize rituximab ADCC effects and instead allows for a synergisticcombination. As noted previously, this may be due to ibrutinib'ssecondary irreversible binding to ITK, which is required forFcR-stimulated NK cell function including calcium mobilization, granulerelease, and overall ADCC. H. E. Kohrt, et al., Blood 2014, 123,1957-60. The potential for ibrutinib antagonization of obinutuzumab(GA-101) ADCC as mediated by NK cells was also explored and compared tothe effects of Formula (XVIII).

The NK cell degranulation/ADCC assay was performed using a whole bloodassay with CLL targets added to normal donor whole blood, in thepresence or absence of different doses of Formula (XVIII) and ibrutinib,followed by opsonization with the anti-CD20 antibody obinutuzumab.Ibrutinib was used as a control, and two blinded samples of BTKinhibitors, Formula (XVIII) and a second sample of ibrutinib, wereprovided to the investigators. Degranulation in whole blood wasperformed as follows. CLL targets (MEC-1 cells) were expanded in RPMI1640 medium (Life Technologies, Inc.) with 10% fetal bovine serum (FBS).Exponentially growing cells were used. On the day of the experiment, 8mL of blood was drawn from a normal volunteer into a test tubecontaining desirudin to obtain a final concentration of 50 μg/mL. Awhite blood cell (WBC) count of whole blood was performed. MEC-1 cellswere re-suspended at the concentration of WBC in whole blood (e.g., if6×10⁶ WBC/mL was measured, MEC-1 cells were re-suspended at 6×10⁶cells/mL, to allow for a final WBC:MEC-1 cell ratio of 1:1). Theibrutinib control and two blinded BTK inhibitors were diluted in X-VIVO15 serum-free hematopoietic cell medium (Lonza Group, Ltd.) toconcentrations of 200 μM, 20 μM and 2 μM. 170 μL aliquots ofunmanipulated whole blood were incubated with 10 μL BTK inhibitors orX-VIVO 15 medium for one hour into a plate. Cetuximab and obinutuzumab(GA-101) were diluted in X-VIVO 15 medium to a concentration of 20μg/mL. Equal volumes of MEC-1 cells and antibodies were incubated for 5minutes. After incubation, 20 μL of MEC-1 cells and antibodies was addedto whole blood and the BTK inhibitors/X-VIVO 15 medium (for a finalvolume of 200 μL). The samples were placed in a 5% CO₂ incubator for 4hours at 37° C. The experimental conditions thus achieved a WBC:MEC-1cell ratio of 1:1, with final concentrations of the BTK inhibitors inthe assay of 10 μM, 1 μM and 0.1 μM and final concentrations of theantibodies of 1 μg/mL.

After 4 hours, the samples were mixed gently and 50 μL aliquots wereremoved from each well and placed in fluorescence-activated cell sorting(FACS) test tubes. A 20 μL aliquot of anti-CD56-APC antibody andanti-CD107a-PE antibody was added. The samples were incubated for 20minutes at room temperature in the dark. An aliquot of 2 mL of FACSlysing solution (BD Biosceinces) was added. The samples were againincubated for 5 minutes, and then centrifuged at 2000 rpm for 5 minutes.Supernatant was discarded and the cell pellet was resuspended in 500 μLof PBS. The samples were analyzed on the flow cytometer for CD107a⁺ NKcells (CD56⁺).

The NK cell degranulation results are summarized in FIG. 98 for n=3experiments, which shows the effects on whole blood after pretreatmentfor 1 hour with the BTK inhibitors at the concentrations shown andsubsequent stimulation with MEC-1 opsonised with obinutuzumab orcetuximab at 1 μg/mL for 4 hours. A strong reduction in the percentageof CD56⁺/CD107a⁺ NK cells is observed using ibrutinib (both as a controland blinded BTK inhibitor), which indicates that ibrutinib undesirablyantagonizes NK cells. In contrast, Formula (XVIII) shows littleantagonism towards NK cells, and had a minimal effect onobinutuzumab-stimulated NK cell degranulation while ibrutinib reducedobinutuzumab-stimulated NK degranulation by greater than 40%. Theseresults support the synergistic combination of obinutuzumab and Formula(XVIII) in treatment of human B cell malignancies.

Example 9—Preclinical Characteristics of BTK Inhibitors

The BTK inhibitor ibrutinib((1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one)is a first-generation BTK inhibitor. In clinical testing as amonotherapy in subjects with hematologic malignancies, ibrutinib wasgenerally well tolerated at dose levels through 840 mg (the highest dosetested). Advani, et al., J. Clin. Oncol. 2013, 31, 88-94; Byrd, et al.,N. Engl. J. Med. 2013, 369, 32-42; Wang, et al., N. Engl. J. Med. 2013,369, 507-16. No maximum tolerated dose (MTD) was apparent within thetested dose range. Furthermore, subjects typically found the drugtolerable over periods extending to >2 years. No subject had tumor lysissyndrome. No overt pattern of myelosuppression was associated withibrutinib treatment. No drug-related reductions in circulating CD4⁺ Tcells or serum immunoglobulins were noted. Adverse events with anapparent relationship to study drug included diarrhea and rash.

In subjects with heavily pretreated non-Hodgkin lymphoma (NHL),ibrutinib showed substantial antitumor activity, inducing durableregressions of lymphadenopathy and splenomegaly in most subjects.Improvements in disease-associated anemia and thrombocytopenia wereobserved. The pattern of changes in subjects with CLL was notable.Single-active pharmaceutical ingredient ibrutinib caused rapid andsubstantial reductions in lymph node size concomitant with aredistribution of malignant sites into the peripheral blood. Anasymptomatic absolute lymphocyte count (ALC) increase was observed thatwas maximal during the first few months of treatment and generallydecreased thereafter but could be persistent in some subjects or couldbe seen repeatedly in subjects who had interruption and resumption ofdrug therapy.

Collectively, these data with ibrutinib support the potential benefitsof selective BTK inhibition in the treatment of subjects with relapsedlymphoid cancers. However, while highly potent in inhibiting BTK,ibrutinib has also shown in vitro activity against other kinases with acysteine in the same position as Cys481 in BTK, to which the drugcovalently binds. For example, ibrutinib inhibits epidermal growthfactor receptor (EGFR), which may be the cause of ibrutinib-relateddiarrhea and rash. In addition, it is a substrate for both cytochromeP450 (CYP) enzymes 3A4/5 and 2D6, which increases the possibility ofdrug-drug interactions. These liabilities support the development ofalternative BTK inhibitors for use in the therapy of lymphoid cancer.

The preclinical selectivity and potency characteristics of thesecond-generation BTK inhibitor of Formula (XVIII) were compared to thefirst-generation BTK inhibitor ibrutinib. In Table 7, a kinome screen(performed by Life Technologies or based on literature data) is shownthat compares these compounds.

TABLE 7 Kinome Screen for BTK Inhibitors (IC₅₀, nM) Ibrutinib (Formula3F-Cys Kinase Formula (XVIII) (XX-A)) Btk 3.1 0.5 Tec 29 78 Bmx 39 0.80Itk >1000 10.7 Txk 291 2.0 EGFR >1000 5.6 ErbB2 912 9.4 ErbB4 13.2 2.7Blk >1000 0.5 JAK-3 >1000 16.1

The results shown in Table 7 are obtained from a 10 point biochemicalassay generated from 10 point concentration curves. The BTK inhibitor ofFormula (XVIII) shows much greater selectivity for BTK compared to otherkinases than ibrutinib.

A comparison of the in vivo potency results for the BTK inhibitors ofFormula (XVIII) and ibrutinib is shown in FIG. 99. CD86 and CD69 arecell surface proteins that are BCR activation markers. To obtain the invivo potency results, mice were gavaged at increasing drug concentrationand sacrificed at one time point (3 hours post-dose). BCR was stimulatedwith IgM and the expression of activation marker CD69 and CD86 aremonitored by flow cytometry and to determine EC₅₀ values.

In vitro and in vivo safety pharmacology studies with Formula (XVIII)have demonstrated a favorable nonclinical safety profile. When screenedat 10 LM in binding assays evaluating interactions with 80 knownpharmacologic targets such as G-protein-coupled receptors, nuclearreceptors, proteases, and ion channels, Formula (XVIII) showssignificant activity only against the A3 adenosine receptor; follow-updose-response experiments indicated a IC₅₀ of 2.7 μM, suggesting a lowclinical risk of off-target effects. Formula (XVIII) at 10 μM showed noinhibition of in vitro EGFR phosphorylation in an A431 human epidermoidcancer cell line whereas ibrutinib had an IC₅₀ of 66 nM. The in vitroeffect of Formula (XVIII) on human ether-à-go-go-related gene (hERG)channel activity was investigated in vitro in human embryonic kidneycells stably transfected with hERG. Formula (XVIII) inhibited hERGchannel activity by 25% at 10 μM, suggesting a low clinical risk thatFormula (XVIII) would induce clinical QT prolongation as predicted bythis assay. Formula (XVIII) was well tolerated in standard in vivo GoodLaboratory Practices (GLP) studies of pharmacologic safety. A functionalobservation battery in rats at doses through 300 mg/kg (the highest doselevel) revealed no adverse effects on neurobehavioral effects or bodytemperature at any dose level. A study of respiratory function in ratsalso indicated no treatment-related adverse effects at doses through 300mg/kg (the highest dose level). In a cardiovascular function study inawake telemeterized male beagle dogs, single doses of Formula (XVIII) atdose levels through 30 mg/kg (the highest dose level) induced nomeaningful changes in body temperature, cardiovascular, orelectrocardiographic (ECG) (including QT interval) parameters. Theresults suggest that Formula (XVIII) is unlikely to cause seriousoff-target effects or adverse effects on critical organ systems.

The drug-drug interaction potential of Formula (XVIII) was alsoevaluated. In vitro experiments evaluating loss of parent drug ascatalyzed by CYPs indicated that Formula (XVIII) is metabolized byCYP3A4. In vitro metabolism studies using mouse, rat, dog, rabbit,monkey, and human hepatocytes incubated with ¹⁴C-labeled Formula (XVIII)indicated two mono-oxidized metabolites and a glutathione conjugate. Nounique human metabolite was identified. Preliminary evaluations ofmetabolism in the plasma, bile, and urine of rats, dogs, and monkeysindicated metabolic processes of oxidation, glutathione binding, andhydrolysis. It was shown that Formula (XVIII) binds to glutathione butdoes not deplete glutathione in vitro. Nonclinical CYP interactionstudies data indicate that Formula (XVIII) is very unlikely to causeclinical drug-drug interactions through alteration of the metabolism ofdrugs that are substrates for CYP enzymes.

The in vitro potency in whole blood of Formula (XVIII), ibrutinib andCC-292 in inhibiting signals through the B cell receptor was alsoassessed. Blood from four healthy donors was incubated for 2 hours withthe compounds shown over a concentration range, and then stimulated withanti-human IgD [10 μg/mL] for 18 hours. The mean fluorescent intensity(MFI) of CD69 (and CD86, data not shown) on gated CD19+ B cells wasmeasured by flow cytometry. MFI values were normalized so that 100%represents CD69 level in stimulated cells without inhibitor, while 0%represents the unstimulated/no drug condition. The results are shown inFIG. 100. The EC₅₀ values obtained were 8.2 nM (95% confidence interval:6.5-10.3), 6.1 nM (95% confidence interval: 5.2-7.2), and 121 nM (95%confidence interval: 94-155) for Formula (XVIII), ibrutinib, and CC-292,respectively.

The EGF receptor phosphorylation in vitro was also determined forFormula (XVIII) and ibrutinib. Epidermoid carcinoma A431 cells wereincubated for 2 h with a dose titration of Formula (XVIII) or ibrutinib,before stimulation with EGF (100 ng/mL) for 5 min to induce EGFRphosphorylation (p-EGFR). Cells were fixed with 1.6% paraformaldehydeand permeabilized with 90% MeOH. Phosphoflow cytometry was performedwith p-EGFR (Y1069). MFI values were normalized so that 100% representsthe p-EGFR level in stimulated cells without inhibitor, while 0%represents the unstimulated/no drug condition. The results are shown inFIG. 101. EGF-induced p-EGFR inhibition was determined to be 7% at 10 μMfor Formula (XVIII), while ibrutinib has an EC₅₀ of 66 nM. The much morepotent inhibition of EGF-induced p-EGFR by ibrutinib may be associatedwith increased side effects including diarrhea and rash.

Example 10—Clinical Study of a BTK Inhibitor in Leukemia/Lymphoma andEffects on Bone Marrow and Lymphoid Microenvironments

Clinical studies have shown that targeting the BCR signaling pathway byinhibiting BTK produces significant clinical benefit in patients withnon-Hodgkin's lymphoma (NHL). The second generation BTK inhibitor,Formula (XVIII), achieves significant oral bioavailability and potency,and has favorable preclinical characteristics, as described above. Thepurpose of this study is to evaluate the safety and efficacy of thesecond generation BTK inhibitor of Formula (XVIII) in treating subjectswith chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma(SLL).

The design and conduct of this study is supported by an understanding ofthe history and current therapies for subjects with lymphoid cancers;knowledge of the activity and safety of a first-generation BTKinhibitor, ibrutinib, in subjects with hematologic cancers; and theavailable nonclinical information regarding Formula (XVIII). Thecollective data support the following conclusions. BTK expression playsan important role in the biology of lymphoid neoplasms, which representserious and life-threatening disorders with continuing unmet medicalneed. Clinical evaluation of Formula (XVIII) as a potential treatmentfor these disorders has sound scientific rationale based on observationsthat the compound selectively abrogates BTK activity and shows activityin nonclinical models of lymphoid cancers. These data are supported byclinical documentation that ibrutinib, a first-generation BTK inhibitor,is clinically active in these diseases. Ibrutinib clinical data andFormula (XVIII) nonclinical safety pharmacology and toxicology studiessupport the safety of testing Formula (XVIII) in subjects with B cellmalignancies.

The primary objectives of the clinical study are as follows: (1)establish the safety and the MTD of orally administered Formula (XVIII)in subjects with CLL/SLL; (2) determine pharmacokinetics (PK) of orallyadministered Formula (XVIII) and identification of its majormetabolite(s); and (3) measure pharmacodynamic (PD) parameters includingdrug occupancy of BTK, the target enzyme, and effect on biologic markersof B cell function.

The secondary objective of the clinical study is to evaluate tumorresponses in patients treated with Formula (XVIII).

This study is a multicenter, open-label, nonrandomized, sequentialgroup, dose escalation study. The following dose cohorts will beevaluated:

Cohort 1: 100 mg/day for 28 days (=1 cycle)

Cohort 2: 175 mg/day for 28 days (=1 cycle)

Cohort 3: 250 mg/day for 28 days (=1 cycle)

Cohort 4: 350 mg/day for 28 days (=1 cycle)

Cohort 5: 450 mg/day for 28 days (=1 cycle)

Cohort 6: To be determined amount in mg/day for 28 days (=1 cycle)

Each cohort will be enrolled sequentially with 6 subjects per cohort. If≤1 dose-limiting toxicity (DLT) is observed in the cohort during Cycle1, escalation to the next cohort will proceed. Subjects may be enrolledin the next cohort if 4 of the 6 subjects enrolled in the cohortcompleted Cycle 1 without experiencing a DLT, while the remaining 2subjects are completing evaluation. If ≥2 DLTs are observed during Cycle1, dosing at that dose and higher will be suspended and the MTD will beestablished as the previous cohort. The MTD is defined as the largestdaily dose for which fewer than 33% of the subjects experience a DLTduring Cycle 1. Dose escalation will end when either the MTD is achievedor at 3 dose levels above full BTK occupancy, whichever occurs first.Full BTK occupancy is defined as Formula (XVIII) active-site occupancyof >80% (average of all subjects in cohort) at 24 hours postdose. Shouldescalation to Cohort 6 be necessary, the dose will be determined basedon the aggregate data from Cohorts 1 to 5, which includes safety,efficacy, and PK/PD results. The dose for Cohort 6 will not exceed 900mg/day.

Treatment with Formula (XVIII) may be continued for >28 days untildisease progression or an unacceptable drug-related toxicity occurs.Subjects with disease progression will be removed from the study. Allsubjects who discontinue study drug will have a safety follow-up visit30 (±7) days after the last dose of study drug unless they have startedanother cancer therapy within that timeframe. Radiologic tumorassessment will be done at screening and at the end of Cycle 2, Cycle 4,and Cycle 12 and at investigator discretion. Confirmation of completeresponse (CR) will require bone marrow analysis and radiologic tumorassessment. For subjects who remain on study for >11 months, a mandatorybone marrow aspirate and biopsy is required in Cycle 12 concurrent withthe radiologic tumor assessment.

All subjects will have standard hematology, chemistry, and urinalysissafety panels done at screening. This study also includes pancreaticfunction assessment (serum amylase and serum lipase) due to thepancreatic findings in the 28-day GLP rat toxicity study. Once dosingcommences, all subjects will be evaluated for safety once weekly for thefirst 4 weeks, every other week for Cycle 2, and monthly thereafter.Blood samples will be collected during the first week of treatment forPK/PD assessments. ECGs will be done at screening, and on Day 1-2, 8,15, 22, 28 of Cycle 1, Day 15 and 28 of Cycle 2, and monthly thereafterthrough Cycle 6. ECGs are done in triplicate for screening only.Thereafter, single ECG tests are done unless a repeat ECG testing isrequired.

Dose-limiting toxicity is defined as any of the following events (if notrelated to disease progression): (1) any Grade ≥3 non-hematologictoxicity (except alopecia) persisting despite receipt of a single courseof standard outpatient symptomatic therapy (e.g., Grade 3 diarrhea thatresponds to a single, therapeutic dose of Imodium® would not beconsidered a DLT); (2) grade ≥3 prolongation of the corrected QTinterval (QTc), as determined by a central ECG laboratory overread; (3)grade 4 neutropenia (absolute neutrophil count [ANC] <500/μL) lasting >7days after discontinuation of therapy without growth factors orlasting >5 days after discontinuation of therapy while on growth factors(i.e., Grade 4 neutropenia not lasting as long as specified will not beconsidered a DLT), (4) grade 4 thrombocytopenia (platelet count<20,000/μL) lasting >7 days after discontinuation of therapy orrequiring transfusion (i.e., Grade 4 thrombocytopenia not lasting aslong as specified will not be considered a DLT), and (5) dosing delaydue to toxicity for >7 consecutive days.

The efficacy parameters for the study include overall response rate,duration of response, and progression-free survival (PFS). The safetyparameters for the study include DLTs and MTD, frequency, severity, andattribution of adverse events (AEs) based on the Common TerminologyCriteria for Adverse Events (CTCAE v4.03) for non-hematologic AEs.Hallek, et al., Blood 2008, 111, 5446-5456.

The schedule of assessments is as follows, with all days stated in thefollowing meaning the given day or +/−2 days from the given day. Aphysical examination, including vital signs and weight, are performed atscreening, during cycle 1 at 1, 8, 15, 22, and 28 days, during cycle 2at 15 and 28 days, during cycles 3 to 24 at 28 days, and at follow up(after the last dose). The screening physical examination includes, at aminimum, the general appearance of the subject, height (screening only)and weight, and examination of the skin, eyes, ears, nose, throat,lungs, heart, abdomen, extremities, musculoskeletal system, lymphaticsystem, and nervous system. Symptom-directed physical exams are donethereafter. Vital signs (blood pressure, pulse, respiratory rate, andtemperature) are assessed after the subject has rested in the sittingposition. Eastern Cooperative Oncology Group (ECOG) status is assessedat screening, during cycle 1 at 1, 8, 15, 22, and 28 days, during cycle2 at 15 and 28 days, during cycles 3 to 24 at 28 days, and at follow up,using the published ECOG performance status indications described inOken, et al., Am. J. Clin. Oncol. 1982, 5, 649-655. ECG testing isperformed at screening, during cycle 1 at 1, 2, 8, 15, 22, and 28 days,during cycle 2 at 15 and 28 days, during cycles 3 to 24 at 28 days, andat follow up. The 12-lead ECG test will be done in triplicate (≥1 minuteapart) at screening. The calculated QTc average of the 3 ECGs must be<480 ms for eligibility. On cycle 1, day 1 and cycle 1, day 8, singleECGs are done predose and at 1, 2, 4, and 6 hours postdose. The singleECG on Cycle 1 Day 2 is done predose. On cycle 1, day 15, day 22, andday 28, a single ECG is done 2 hours post-dose. Starting with cycle 2, asingle ECG is done per visit. Subjects should be in supine position andresting for at least 10 minutes before study-related ECGs. Twoconsecutive machine-read QTc >500 ms or >60 ms above baseline requirecentral ECG review. Hematology, including complete blood count withdifferential and platelet and reticulocyte counts, is assesed atscreening, during cycle 1 at 1, 8, 15, 22, and 28 days, during cycle 2at 15 and 28 days, during cycles 3 to 24 at 28 days, and at follow up.Serum chemistry is assesed at screening, during cycle 1 at 1, 8, 15, 22,and 28 days, during cycle 2 at 15 and 28 days, during cycles 3 to 24 at28 days, and at follow up. Serum chemistry includes albumin, alkalinephosphatase, ALT, AST, bicarbonate, blood urea nitrogen (BUN), calcium,chloride, creatinine, glucose, lactate dehydrogenase (LDH), magnesium,phosphate, potassium, sodium, total bilirubin, total protein, and uricacid. Cell counts and serum immunoglobulin are performed at screening,at cycle 2, day 28, and at every 6 months thereafter until last dose andinclude T/B/NK/monocyte cell counts (CD3, CD4, CD8, CD14, CD19, CD19,CD16/56, and others as needed) and serum immunoglobulin (IgG, IgM, IgA,and total immunoglobulin). Bone marrow aspirates are performed at cycle12. Pharmacodynamics samples are drawn during cycle 1 at 1, 2, and 8days, and at follow up. On days 1 and 8, pharmacodynamic samples aredrawn pre-dose and 4 hours (±10 minutes) post-dose, and on day 2,pharmacodynamic samples are drawn pre-dose. Pharmacokinetics samples aredrawn during cycle 1 at 1, 2, 8, 15, 22, and 28 days. Pharmacokineticsamples for Cycle 1 Day 1 are drawn pre-dose and at 0.5, 1, 2, 4, 6 and24 hours (before dose on Day 2) post-dose. Samples for Cycle 1 Day 8 aredrawn pre-dose and at 0.5, 1, 2, 4, and 6 hours post-dose. On Cycle 1Day 15, 22, and 28, a PK sample is drawn pre-dose and the second PKsample must be drawn before (up to 10 minutes before) the ECGacquisition, which is 2 hours postdose. Pretreatment radiologic tumorassessments are performed within 30 days before the first dose. Acomputed tomography (CT) scan (with contrast unless contraindicated) isrequired of the chest, abdomen, and pelvis. In addition, a positronemission tomography (PET) or PET/CT must done for subjects with SLL.Radiologic tumor assessments are mandatory at the end of Cycle 2 (−7days), Cycle 4 (−7 days), and Cycle 12 (−7 days). Otherwise, radiologictumor assessments are done at investigator discretion. A CT (withcontrast unless contraindicated) scan of the chest, abdomen, and pelvisis required for subjects with CLL. In addition, a PET/CT is required insubjects with SLL. Bone marrow and radiologic assessments are bothrequired for confirmation of a complete response (CR). Clinicalassessments of tumor response should be done at the end of Cycle 6 andevery 3 months thereafter. Molecular markers are measured at screening,and include interphase cytogenetics, stimulated karyotype, IgHVmutational status, Zap-70 methylation, and beta-2 microglobulin levels.Urinalysis is performed at screening, and includes pH, ketones, specificgravity, bilirubin, protein, blood, and glucose. Other assessments,including informed consent, eligibility, medical history, and pregnancytest are done at the time of screening.

The investigator rates the subject's response to treatment based onrecent guidelines for CLL, as given in Hallek, et al., Blood 2008, 111,5446-56, and for SLL, as given in Cheson, et al., J. Clin. Oncol. 2007,25, 579-586. The response assessment criteria for CLL are summarized inTable 8.

TABLE 8 Response Assessment Criteria for CLL. Abbreviations: ANC =absolute neutrophil count; CR = complete remission; CRi = CR withincomplete blood count recovery; PR = partial remission. Re- Bone MarrowNodes, Liver, and sponse Peripheral Blood (if performed) Spleen^(a) CRLymphocytes <4 × 10⁹/L Normocellular Normal (e.g., no ANC >1.5 ×10⁹/L^(b) <30% lymph nodes Platelets >100 × 10⁹/L^(b) lymphocytes >1.5cm) Hemoglobin >11.0 g/dL No B-lymphoid (untransfused)^(b) nodules CRiLymphocytes <4 × 10⁹/L Hypocellular Normal (e.g., no Persistent anemia,<30% lymph nodes thrombocytopenia, or lymphocytes >1.5 cm) neutropeniarelated to drug toxicity PR Lymphocytes ≥50% Not assessed ≥50% reductionin decrease from baseline lymphadenopathy^(c) ANC >1.5 × 10⁹/L and/or inspleen or or liver enlargement Platelets >100 × 10⁹/L or 50% improvementover baseline^(b) or Hemoglobin >11.0 g/dL or 50% improvement overbaseline (untransfused)^(b) ^(a)Computed tomography (CT) scan of abdomenpelvis, and chest is required for this evaluation ^(b)Without need forexogenous growth factors ^(c)In the sum products of ≤6 lymph nodes or inthe largest diameter of the enlarged lymph node(s) detected beforetherapy and no increase in any lymph node or new enlarged lymph nodes

The response assessment criteria for SLL are summarized in Table 9.

TABLE 9 Response Assessment Criteria for SLL. Abbreviations: CR =complete remission, CT = computed tomography, FDG =[¹⁸F]fluorodeoxyglucose, PET = positron-emission tomography, PR =partial remission, SD = stable disease, SPD = sum of the product of thediameters. Response Definition Nodal Masses Spleen, Liver Bone Marrow CRDisappearance (a) FDG-avid or PET Not palpable, If infiltrate present ofall evidence positive prior to nodules at screening, of disease therapy;mass of any disappeared infiltrate cleared on size permitted if PETrepeat biopsy; if negative indeterminate by (b) Variably FDG-avidmorphology, or PET negative; immunohisto- regression to normal chemistryshould be size on CT negative PR Regression of ≥50% decrease in SPD ≥50%decrease Irrelevant if measurable of up to 6 largest in SPD of positiveprior to disease and no dominant masses; no nodules (for therapy; celltype new sites increase in size of other single nodule in should bespecified nodes greatest (a) FDG-avid or PET transverse positive priorto diameter); no therapy; ≥1 PET increase in size positive at previouslyof liver or involved site spleen (b) Variably FDG-avid or PET negative;regression on CT SD Failure to (a) FDG-avid or PET attain CR/PR positiveprior to or progressive therapy; PET positive disease at prior sites ofdisease, and no new sites on CT or PET (b) Variably FDG avid or PETnegative; no change in size of previous lesions on CT

The PK parameters of the study are as follows. The plasma PK of Formula(XVIII) and a metabolite is characterized using noncompartmentalanalysis. The following PK parameters are calculated, whenever possible,from plasma concentrations of Formula (XVIII):

-   -   AUC_((0-t)): Area under the plasma concentration-time curve        calculated using linear trapezoidal summation from time 0 to        time t, where t is the time of the last measurable concentration        (Ct),    -   AUC₍₀₋₂₄₎: Area under the plasma concentration-time curve from 0        to 24 hours, calculated using linear trapezoidal summation,    -   AUC_((0-∞)): Area under the plasma concentration-time curve from        0 to infinity, calculated using the formula:        AUC_((0-∞))=AUC_((0-t))+Ct/λz, where λz is the apparent terminal        elimination rate constant,    -   C_(max): Maximum observed plasma concentration,    -   T_(max): Time of the maximum plasma concentration (obtained        without interpolation),    -   t_(1/2): Terminal elimination half-life (whenever possible),    -   λ_(z): Terminal elimination rate constant (whenever possible),    -   Cl/F: oral clearance.

The PD parameters of the study are as follows. The occupancy of BTK byFormula (XVIII) are measured in peripheral blood mononuclear cells(PBMCs) with the aid of a biotin-tagged Formula (XVIII) analogue probe.The effect of Formula (XVIII) on biologic markers of B cell functionwill also be evaluated.

The statistical analysis used in the study is as follows. No formalstatistical tests of hypotheses are performed. Descriptive statistics(including means, standard deviations, and medians for continuousvariables and proportions for discrete variables) are used to summarizedata as appropriate.

The following definitions are used for the safety and efficacy analysissets: Safety analysis set: All enrolled subjects who receive ≥1 dose ofstudy drug; Per-protocol (PP) analysis set: All enrolled subjects whoreceive ≥1 dose of study drug and with ≥1 tumor response assessmentafter treatment. The safety analysis set will be used for evaluating thesafety parameters in this study. The PP analysis sets will be analyzedfor efficacy parameters in this study.

No imputation of values for missing data is performed except for missingor partial start and end dates for adverse events and concomitantmedication will be imputed according to prespecified, conservativeimputation rules. Subjects lost to follow-up (or drop out) will beincluded in statistical analyses to the point of their last evaluation.

The safety endpoint analysis was performed as follows. Safety summarieswill include summaries in the form of tables and listings. The frequency(number and percentage) of treatment emergent adverse events will bereported in each treatment group by Medical Dictionary for RegulatoryActivities (MedDRA) System organ Class and Preferred Term. Summarieswill also be presented by the severity of the adverse event and byrelationship to study drug. Laboratory shift tables containing countsand percentages will be prepared by treatment assignment, laboratoryparameter, and time. Summary tables will be prepared for each laboratoryparameter. Figures of changes in laboratory parameters over time will begenerated. Vital signs, ECGs, and physical exams will be tabulated andsummarized.

Additional analyses include summaries of subject demographics, baselinecharacteristics, compliance, and concurrent treatments. Concomitantmedications will be coded according to the World Health organization(WHO) Drug Dictionary and tabulated.

The analysis of efficacy parameters was performed as follows. The pointestimate of the overall response rate will be calculated for the PPanalysis set. The corresponding 95% confidence interval also will bederived. The duration of overall response is measured from the timemeasurement criteria are met for CR or PR (whichever is first recorded)until the first date that recurrent or progressive disease isobjectively documented (taking as reference for progressive disease thesmallest measurements recorded since the treatment started).Kaplan-Meier methodology will be used to estimate event-free curves andcorresponding quantiles (including the median). Progression-freesurvival is measured from the time of first study drug administrationuntil the first date that recurrent or progressive disease isobjectively documented (taking as reference for progressive disease thesmallest measurements recorded since the treatment started).Kaplan-Meier methodology will be used to estimate the event-free curvesand corresponding quantiles (including the median).

The study scheme is a seqential cohort escalation. Each cohort consistsof six subjects. The sample size of the study is 24 to 36 subjects,depending on dose escalation into subsequent cohorts. Cohort 1 (N=6)consists of Formula (XVIII), 100 mg QD for 28 days. Cohort 2 (N=6)consists of Formula (XVIII), 175 mg QD for 28 days. Cohort 3 (N=6)consists of Formula (XVIII), 250 mg QD for 28 days. Cohort 4 (N=6)consists of Formula (XVIII), 350 mg QD for 28 days. Cohort 5 (N=6)consists of Formula (XVIII), 450 mg QD for 28 days. Cohort 6 (N=6)consists of Formula (XVIII), at a dose to be determined QD for 28 days.The dose level for Cohort 6 will be determined based on the safety andefficacy of Cohorts 1 to 5, and will not exceed 900 mg/day. Escalationwill end with either the MTD cohort or three levels above full BTKoccupancy, whichever is observed first. An additional arm of the studywill explore 100 mg BID dosing. Treatment with oral Formula (XVIII) maybe continued for greater than 28 days until disease progression or anunacceptable drug-related toxicity occurs.

The inclusion criteria for the study are as follows: (1) men and women≥18 years of age with a confirmed diagnosis of CLL/SLL, which hasrelapsed after, or been refractory to, ≥2 previous treatments forCLL/SLL; however, subjects with 17p deletion are eligible if they haverelapsed after, or been refractory to, 1 prior treatment for CLL/SLL;(2) body weight ≥60 kg, (3) ECOG performance status of ≤2; (4) agreementto use contraception during the study and for 30 days after the lastdose of study drug if sexually active and able to bear children; (5)willing and able to participate in all required evaluations andprocedures in this study protocol including swallowing capsules withoutdifficulty; or (6) ability to understand the purpose and risks of thestudy and provide signed and dated informed consent and authorization touse protected health information (in accordance with national and localsubject privacy regulations).

The dosage form and strength of Formula (XVIII) used in the clinicalstudy is a hard gelatin capsules prepared using standard pharmaceuticalgrade excipients (microcrystalline cellulose) and containing 25 mg ofFormula (XVIII) each. The color of the capsules is Swedish orange. Theroute of administration is oral (per os, or PO). The dose regimen isonce daily or twice daily, as defined by the cohort, on an empty stomach(defined as no food 2 hours before and 30 minutes after dosing).

The baseline characteristics for the patients enrolled in the clinicalstudy are given in Table 10.

TABLE 10 Relapsed/refractory CLL baseline characteristics.Characteristic CLL (N = 44) Patient Demographics Age (years), median(range)   62 (45-84) Sex, men (%) 33 (75) Prior therapies, median   3(1-10) (range), n ≥3 prior therapies, n (%) 26 (59) Clinical DetailsECOG performance status ≥1 28 (63) (%) Rai stage III/IV 16 (36) Bulkydisease ≥5 cm, n (%) 15 (34) Cytopenia at baseline 33 (75) CytogenicStatus Chromosome 11q22.3 deletion 18 (41) (Del 11q), n (%) Chromosome17p13.1 (Del 19 (34) 17p), n (%) IgV_(H) status (unmutated), n (%) 28(64)

The results of the clinical study in relapsed/refractory CLL patientsare summarized in Table 11.

TABLE 11 Activity of Formula (XVIII) in relapsed/refractory CLL. n (%)All Cohorts 100 mg QD 175 mg QD 250 mg QD 100 mg BID 400 mg QD (N = 31)(N = 8) (N = 8) (N = 7) (N = 3) (N = 5) PR 22 (71) 7 (88) 5 (63) 5 (71) 3 (100) 2 (40) PR + L  7 (23) 0 (0)  3 (37) 2 (29) 0 (0) 2 (40) SD 2(6) 1 (12) 0 (0)  0 (0)  0 (0) 1 (20) PD 0 (0) 0 (0)  0 (0)  0 (0)  0(0) 0 (0)  Median (range) Cycles    7.3 (3.0-10.8)   10.0 (9.0-10.8)  8.6 (3.0-8.8)   7.0 (7.0-7.3)     5.2 (4.7-5.5)   5.0 (4.8-5.5) (PR =partial response; PR + L = partial response with lymphocytosis; SD =stable disease; PD = progressive disease.)

FIG. 100 shows the median % change in ALC and SPD from baseline in theclinical study of Formula (XVIII), plotted in comparison to the resultsreported for ibrutinib in FIG. 1A of Byrd, et al., N. Engl. J. Med.2013, 369, 32-42. The results show that Formula (XVIII) leads to a morerapid patient response in CLL than corresponding treatment withibrutinib. This effect is illustrated, for example, by the median %change in SPD, which achieved the same status in the present study at 7months of treatment with Formula (XVIII) as compared to 18 months foribrutinib. The % change in SPD observed in the different cohorts (i.e.by dose and dosing regimen) is shown in FIG. 101, and in all cases showssignificant responses.

A Kaplan-Meier curve showing PFS from the clinical CLL study of Formula(XVIII) is shown in FIG. 102. A comparison of survival curves wasperformed using the Log-Rank (Mantle-Cox) test, with a p-value of 0.0206indicating that the survival curves are different. The number ofpatients at risk is shown in FIG. 103. Both FIG. 102 and FIG. 103 showthe results for Formula (XVIII) in comparison to the results reportedfor ibrutinib in Byrd, et al., N. Engl. J. Med. 2013, 369, 32-42. Animprovement in survival and a reduction in risk are observed in CLLpatients treated with Formula (XVIII) in comparison to patients treatedwith ibrutinib.

Based on the data and comparisons shown in FIG. 100 to FIG. 103, the CLLstudy with Formula (XVIII) showed that the efficacy of Formula (XVIII)was surprisingly superior to that of ibrutinib.

In the literature study of ibrutinib, increased disease progression wasassociated with patients with high-risk cytogenetic lesions (17p13.1deletion or 11q22.3 deletion), as shown in FIG. 3A in Byrd, et al., N.Engl. J. Med. 2013, 369, 32-42, which shows ibrutinib PFS including PFSbroken down by genetic abnormality. The 17p and 11q deletions arevalidated high-risk characteristics of CLL, and the 17p deletion is thehighest risk. In FIG. 104, the PFS is shown for Formula (XVIII) inpatients with the 17p deletion in comparison to the results obtained foribrutinib in Byrd, et al., N. Engl. J. Med. 2013, 369, 32-42. A p-valueof 0.0696 was obtained. In FIG. 105, the number of patients at risk withthe 17p deletion is compared. To date, no 17p patients have progressedon Formula (XVIII).

The adverse events observed in the clinical study in relapsed/refractoryCLL are given in Table 12. No DLTs were observed. The MTD was notreached. No treatment-related serious adverse events (SAEs) wereobserved. No prophylactic antivirals or antibiotics were needed.

TABLE 12 Treatment-related adverse events reported in the clinical studyof Formula (XVIII) in relapsed/refractory CLL. (Reported in ≥5% ofpatients.) Adverse Events (Treatment- Related), n (%) Grade All (N = 44)Headache 1/2  7 (16) Increased tendency 1  6 (14) to bruise Diarrhea 1 4(9) Petechiae 1 3 (7)

The clinical study of Formula (XVIII) thus showed other unexpectedlysuperior results compared to ibrutinib therapy. A lack of lymphocytosiswas observed in the study. Furthermore, only grade 1 AEs were observed,and these AEs were attributable to the high BTK selectivity of Formula(XVIII).

BTK target occupany was measured for relapsed/refractory CLL patientswith the results shown in FIG. 106. For 200 mg QD dosing of the BTKinhibitor of Formula (XVIII), about 94%-99% BTK occupancy was observed,with superior 24 hour coverage and less inter-patient variability alsoobserved. For 420 mg and 840 mg QD of the BTK inhibitor ibrutinib,80%-90% BTK occupancy was observed, with more inter-patient variabilityand capped occupancy. These results indicate that the BTK inhibitor ofFormula (XVIII) achieves superior BTK occupancy in CLL patients thanibrutinib.

The effects of Formula (XVIII) on cell subset percentages were alsoevaluated using flow cytometry analysis of peripheral blood, with theresults shown in FIG. 107, FIG. 108, FIG. 109, FIG. 110, FIG. 111, andFIG. 112. PBMC samples from CLL patient samples drawn prior to (predose)and after 28 days of dosing with Formula (XVIII) were compared forpotential changes in cell subsets. PBMCs were stained with monoclonalantibodies conjugated to fluorescent tags (flourochromes) to identifycell subsets via flow cytometry. Non-viable cells were excluded from theanalysis using the dye 7-aminoactinomycin D (7-AAD). To produce themetric of percent change, the following steps were taken. First, eachcell subset was defined by hierarchical flow cytometry gating. Then, thechange in frequency (between day 1 and day 28) was calculated for eachcell subset. MDSC subsets were measured as a % of all myeloid cells. Tcell subsets were measured as a % of all CD3⁺ cells, and NK cells weremeasured as a % of all live CD45⁺ cells. In FIG. 107 and FIG. 108, theresults show the % change in MDSC (monocytic) level over 28 days versus% ALC change at cycle 1 day 28 (C1D28) and at cycle 2 day 28 (C2D28). Acycle is 28 days. A trend is observed wherein patients with decreasingALC % had increasing MDSC (monocytic) %. This may include patients whohad quickly resolving lymphocytosis and those with no initiallymphocytosis. This provides evidence that treatment with Formula(XVIII) mobilizes MDSCs and thus affects the CLL tumor microenvironmentin marrow and lymph nodes, which is an unexpected indication of superiorefficacy. In FIG. 109 and FIG. 110, the results show the % change in NKcell level over 28 days versus % ALC change, measured at C1D28 or C2D28,and similar trends are observed wherein patients with decreasing ALC %had increasing NK cell %. This may include patients who had quicklyresolving lymphocytosis and those having no initial lymphocytosis. Theeffects in FIG. 107 to FIG. 110 are observed in multiple cohorts, atdoses including 100 mg BID, 200 mg QD, and 400 mg QD. In FIG. 111 andFIG. 112, the effects on NK cells and MDSC cells are compared to anumber of other markers versus % change in ALC at C1D28 and C2D28. Theseother markers include CD4+ T cells, CD8+ T cells, CD4+/CD8+ T cellratio, NK-T cells, PD-1+ CD4+ T cells, and PD-1+ CD8+ T cells. Theeffects on NK cells and MDSC cells are observed to be much morepronounced than on any of these other markers.

These results suggest that after Formula (XVIII) administration, the CLLmicroenvironment undergoes a change wherein NK cells and monocytic MDSCsubsets increase in frequency in the peripheral blood in patients withfalling ALC counts, an important clinical parameter in CLL. The NK cellincrease may reflect an overall increase in cytolytic activity againstB-CLL resulting in the ALC % to drop. The increase in MDSC % in theblood may be due to a movement of these cells out of the lymph nodes,spleen, and bone marrow, which are all possible sites of CLLproliferation. Fewer MDSCs at the CLL proliferation centers would likelyresult in a reduced immunosuppressive microenvironment leading to anincrease in cell-mediated immunity against the tumor, decreased tumorproliferation, and eventually lower ALC % in the circulation.

Updated clinical results from the CLL study are shown in FIG. 115 toFIG. 120. FIG. 115 shows an update of the data presented in FIG. 102.FIG. 116 shows an update of the data presented in FIG. 108, and includesBID dosing results. Formula (XVIII) 200 mg QD dosing resulted in 94%-99%BTK occupancy, 24 hour coverage, and less inter-patient variability.Ibrutinib 420 mg and 840 mg QD dosing resulted in 80%-90% BTK occupancy,more inter-patient variability, and capped occupancy. Formula (XVIII)100 mg BID dosing resulted in 97%-99% BTK occupancy, complete BTKcoverage, and less inter-patient variability. The PFS for patients with11p deletions and 17q deletions are illustrated in FIG. 117, FIG. 118,and FIG. 119. Updated SPD results are illustrated in FIG. 120.

Treatment of CLL patients with Formula (XVIII) also resulted inincreased apoptotis, as illustrated in FIG. 121. Apoptotic B-CLL wasdefined by flow cytometry as having cleaved PARP⁺, Caspase 3⁺, CD19⁺,and CD5⁺ phenotypes. 82% of samples tested had a baseline change greaterthan 25%. Treatment of CLL patients also showed that Formula (XVIII)decreased plasma chemokines associated with MDSC homing and retention. Asignificant decrease in CXCL12 and CCL2 levels has been observed inpatients treated with Formula (XVIII), as shown in FIG. 122 and FIG.123, respectively.

Overall, Formula (XVIII) shows superior efficacy to first generation BTKinhibitors such as ibrutinib, or to monotherapy with PI3K-δ inhibitorssuch as idelalisib. Formula (XVIII) has better target occupancy andbetter pharmacokinetic and metabolic parameters than ibrutinib, leadingto improved B cell apoptosis. Furthermore, unlike treatment withibrutinib and PI3K-δ inhibitors, treatment with Formula (XVIII) does notaffect NK cell function. Finally, treatment with Formula (XVIII) leadsto a CLL tumor microenvironmental effect by excluding MDSC cells fromthe marrow and lymph nodes and reducing their number.

Example 11—Clinical Study of a BTK Inhibitor in Leukemia/Lymphoma inCombination with Obinutuzumab (GA-101)

The primary objectives of the study are (1) to determine the overallresponse rate (ORR) at 12 months with the combination of Formula (XVIII)and obinutuzumab in patients with relapsed or refractory CLL, (2) todetermine the ORR at 12 months with the combination of Formula (XVIII)and obinutuzumab in patients with treatment-naive CLL, and (3) toestablish the safety and feasibility of the combination of Formula(XVIII) and obinutuzumab.

The secondary objectives of this study are: (1) to determine thecomplete response (CR) rate and MRD-negative CR rate in previouslyuntreated and relapsed and refractory CLL with this regimen; (2) todetermine the progression-free survival (PFS), time to next treatment(TTNT), and overall survival (OS) with this regimen, (3) to performbaseline analysis of patients enrolled on this trial includingfluorescence in situ hybridization (FISH), stimulated karyotype, Zap-70methylation, and IgV_(H) mutational status and describe relationshipsbetween these biomarkers and ORR or PFS for patients treated with thisregimen; (4) to determine pharmacokinetics (PK) of orally administeredFormula (XVIII); (5) to measure pharmacodynamic (PD) parametersincluding drug occupancy of BTK, change in miR and gene expression onday 8 and 29 of therapy of Formula (XVIII); (6) to determine theinfluence of Formula (XVIII) on NK cell and T cell function in vivo; (7)to assess for serial development of resistance by baseline andlongitudinal assessment of mutations of BTK and PLCG2 at regular followup intervals and by examining diagnosis to relapse samples by wholeexome sequencing; (8) to determine the influence of Formula (XVIII) onemotional distress and quality of life in CLL patients; and (9) todetermine trajectory of psychological and behavioral responses toFormula (XVIII) and covariation with response to therapy.

CLL is the most prevalent form of adult leukemia and has a variableclinical course, where many patients do not require treatment for yearsand have survival equal to age matched controls. Other patients,however, exhibit aggressive disease and have a poor prognosis despiteappropriate therapy. Byrd, et al., Chronic lymphocytic leukemia.Hematology Am. Soc. Hematol. Educ. Program. 2004, 163-183. Whilepatients with early disease have not been shown to have a survivaladvantage with early treatment, most patients will eventually requiretherapy for their disease with the onset of symptoms or cytopenias, anddespite the relatively long life expectancy for early stage disease, CLLremains an incurable disease. Patients diagnosed with or progressing toadvanced disease have a mean survival of 18 months to 3 years.Unfortunately these patients with advanced disease are also morerefractory to conventional therapy.

The treatment of CLL has progressed significantly over the previousdecades. While alkylator therapy was used in the past, randomized trialshave demonstrated a higher response rate and longer progression freesurvival (PFS) with fludarabine and subsequently with fludarabine-andcyclophosphamide-based combinations. O'Brien, et al., Advances in thebiology and treatment of B-cell chronic lymphocytic leukemia. Blood1995, 85, 307-18; Rai, et al., Fludarabine compared with chlorambucil asprimary therapy for chronic lymphocytic leukemia. N. Engl. J. Med. 2000,343, 1750-57; Johnson, et al., Multicentre prospective randomised trialof fludarabine versus cyclophosphamide, doxorubicin, and prednisone(CAP) for treatment of advanced-stage chronic lymphocytic leukaemia. TheFrench Cooperative Group on CLL. Lancet 1996, 347, 1432-38; Leporrier,et al., Randomized comparison of fludarabine, CAP, and ChOP in 938previously untreated stage B and C chronic lymphocytic leukemiapatients. Blood 2001, 98, 2319-25; Catovsky, et al., Assessment offludarabine plus cyclophosphamide for patients with chronic lymphocyticleukaemia (the LRF CLL4 Trial): A randomised controlled trial. Lancet2007, 370, 230-239; Eichhorst, et al., Fludarabine plus cyclophosphamideversus fludarabine alone in first-line therapy of younger patients withchronic lymphocytic leukemia. Blood 2006, 107, 885-91. At the same time,the chimeric anti-CD20 monoclonal antibody rituximab was introduced forthe treatment of CLL. At high doses or with dose intensive treatment,single agent rituximab has shown efficacy; however complete responsesand extended remissions are very rare. O'Brien, et al. Rituximabdose-escalation trial in chronic lymphocytic leukemia. J. Clin. Oncol.2001, 19, 2165-70; Byrd, et al., Rituximab using a thrice weekly dosingschedule in B-cell chronic lymphocytic leukemia and small lymphocyticlymphoma demonstrates clinical activity and acceptable toxicity. Clin.Oncol. 2001, 19, 2153-64. The efficacy of rituximab has been improved bycombining it with traditional cytotoxic agents such as fludarabine orfludarabine and cyclophosphamide, which have produced high CR rates andextended progression free survival (PFS) compared to historicalcontrols. Indeed, a large randomized clinical trial reported by theGerman CLL study group has shown a benefit of the addition of antibodytherapy with rituximab to fludarabine and cyclophosphamide in theprolongation of PFS and OS in patients with untreated CLL. Hallek, etal., Addition of rituximab to fludarabine and cyclophosphamide inpatients with chronic lymphocytic leukaemia: a randomised, open-label,phase 3 trial. Lancet 2010, 376, 1164-74. This encouraging progress intherapy and our understanding of the disease has resulted insignificantly improved response rates and PFS. However, significantimprovements in overall survival (OS) and ultimately cure, remainelusive goals.

While fludarabine based chemoimmunotherapy is standard for youngerpatients, the therapy for older patients is less well defined. In thelarge Phase 2 and 3 trials outlined previously, median ages weretypically in the early-60s, while the average age of patients diagnosedwith CLL is 72, which calls into question whether these results aregeneralizable to the entire CLL population. In fact, the one randomizedPhase 3 trial investigating primary CLL therapy in older patientsdemonstrated that in patients >65 years old, fludarabine is not superiorto chlorambucil. Eichhorst, et al., First-line therapy with fludarabinecompared with chlorambucil does not result in a major benefit forelderly patients with advanced chronic lymphocytic leukemia. Blood 2009,114, 3382-91. This finding was corroborated by a large retrospectivestudy of front-line trials performed by the Alliance for Clinical Trialsin Oncology, which demonstrated again that fludarabine is not superiorto chlorambucil in older patients, but also showed that the addition ofrituximab to chemotherapy was beneficial regardless of age. Woyach, etal., Impact of age on outcomes after initial therapy with chemotherapyand different chemoimmunotherapy regimens in patients with chroniclymphocytic leukemia: Results of sequential cancer and leukemia group Bstudies. J. Clin. Oncol. 2013, 31, 440-7. Two studies have evaluated thecombination of rituximab with chlorambucil, showing that thiscombination is safe and moderately effective. Hillmen, et al., rituximabplus chlorambucil in patients with CD20-positive B-cell chroniclymphocytic leukemia (CLL): Final response analysis of an open-labelPhase II Study, ASH Annual Meeting Abstracts, Blood 2010, 116, 697; Foa,et al., A Phase II study of chlorambucil plus rituximab followed bymaintenance versus observation in elderly patients with previouslyuntreated chronic lymphocytic leukemia: Results of the first interimanalysis, ASH Annual Meeting Abstracts, Blood 2010, 116, 2462.

Recently, the type II glycoengineered CD20 monoclonal antibodyobinutuzumab was introduced. In a Phase 1 trial of previously treatedCLL as monotherapy, this antibody has a 62% response rate including 1MRD-negative complete response, suggesting that alone this antibody maybe more active in CLL than rituximab. Morschhauser, et al., Phase Istudy of R05072759 (GA10) in relapsed/refractory chronic lymphocyticleukemia, ASH Annual Meeting Abstracts. Blood, 2009, 114, 884. TheGerman CLL Study Group (GCLLSG) recently completed a Phase 3 trial ofrituximab and chlorambucil or obinutuzumab and chlorambucil vschlorambucil alone in patients with untreated CLL and significantcomorbidities. In this population, obinutuzumab and chlorambucil (butnot rituximab and chlorambucil) improved OS over chlorambucil alone(hazard ratio 0.41, p=0.002), and obinutuzumab and chlorambucil improvedPFS over rituximab and chlorambucil (median PFS 26.7 months vs 14.9months, p<0.001). Goede, et al., Obinutuzumab plus chlorambucil inpatients with CLL and coexisting conditions, N. Engl. J. Med. 2014, 370,1101-10. On the basis of these favorable data, the combination ofobinutuzumab and chlorambucil is FDA approved as frontline therapy forCLL patients.

Many older patients are also treated with the combination ofbendamustine plus rituximab (BR). Although BR has not been compareddirectly with chlorambucil and rituximab, results of a recent Phase 2trial show an ORR of 88% with a median event free survival of 33.9months and 90.5% OS at 27 months. Fischer, et al., Bendamustine incombination with rituximab for previously untreated patients withchronic lymphocytic leukemia: A multicenter phase II trial of the GermanChronic Lymphocytic Leukemia Study Group. J. Clin. Oncol. 2012, 30,3209-16. These results held for patients >70 years old, and comparefavorably with results published for chlorambucil and rituximab. Whileresults with this regimen appear to be improved over historicalcontrols, outcomes are not as good as those observed in younger patientswith chemoimmunotherapy. Therefore, the optimal therapy for olderpatients remains an unmet need in clinical trials.

Additionally, most patients eventually relapse with their disease andare frequently refractory to existing agents. Patients who relapse aftercombined chemoimmunotherapy have a poor outcome with subsequent standardtherapies. While options for these patients include alemtuzumab,bendamustine, high dose corticosteroids, ofatumumab, and combinationbased approaches, none of these therapies produces durable remissionsthat exceed that observed with first line chemoimmunotherapy. Keating,et al., Therapeutic role of alemtuzumab (Campath-1H) in patients whohave failed fludarabine: results of a large international study. Blood2002, 99, 3554-61; Bergmann, et al., Efficacy of bendamustine inpatients with relapsed or refractory chronic lymphocytic leukemia:results of a phase I/II study of the German CLL Study Group.Haematologica 2005, 90, 1357-64; Thornton P D, Matutes E, Bosanquet A G,et al. High dose methylprednisolone can induce remissions in CLLpatients with p53 abnormalities. Ann. Hematology 2003, 82, 759-65;Coiffier, et al., Safety and efficacy of ofatumumab, a fully humanmonoclonal anti-CD20 antibody, in patients with relapsed or refractoryB-cell chronic lymphocytic leukemia: A phase 1-2 study. Blood 2008, 111,1094-1100; Tsimberidou, et al., Phase I-II study of oxaliplatin,fludarabine, cytarabine, and rituximab combination therapy in patientswith Richter's syndrome or fludarabine-refractory chronic lymphocyticleukemia. J. Clin. Oncol. 2008, 26, 196-203. Several of these therapiesincluding alemtuzumab and high dose steroids are also associated withsignificant toxicities and sustained immunosuppression. Lozanski G,Heerema N A, Flinn lW, et al. Alemtuzumab is an effective therapy forchronic lymphocytic leukemia with p53 mutations and deletions. Blood2004, 103, 3278-81; Osuji, et al., The efficacy of alemtuzumab forrefractory chronic lymphocytic leukemia in relation to cytogeneticabnormalities of p53. Haematologica 2005, 90, 1435-36; Thornton, et al.,High dose methyl prednisolone in refractory chronic lymphocyticleukaemia. Leuk. Lymphoma 1999, 34, 167-70; Bowen, et al.Methylprednisolone-rituximab is an effective salvage therapy forpatients with relapsed chronic lymphocytic leukemia including those withunfavorable cytogenetic features. Leuk Lymphoma 2007, 48, 2412-17;Castro, et al., Rituximab in combination with high-dosemethylprednisolone for the treatment of fludarabine refractory high-riskchronic lymphocytic leukemia. Leukemia 2008, 22, 2048-53.

In an ongoing Phase 1b/2 study, the BTK inhibitor ibrutinib has shownactivity in patients with relapsed or refractory CLL. In patients withrelapsed or refractory CLL and measurable lymphadenopathy, the rate oflymph node shrinkage >50% is 89%. With a median follow-up of 4 months,ORR was 48% due to asymptomatic lymphocytosis, and with longer follow-upof 26 months in patients receiving the 420 mg dose, has improved to 71%,with an additional 20% of patients achieving a partial response withlymphocytosis (PR-L). Byrd, et al., Activity and tolerability of theBruton's tyrosine kinase (Btk) inhibitor PCI-32765 in patients withchronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL):Interim results of a phase Ib/II study. J. Clin. Oncol. ASCO AnnualMeeting Abstracts, 2011, 29, Abstract 6508; Byrd, et al. Targeting BTKwith ibrutinib in relapsed chronic lymphocytic leukemia. N. Engl. J.Med. 2013, 369, 32-42. This lymphocytosis is likely related to B cellrelease from lymph node, spleen and marrow microenvironment due todisruption of homing signals or chemoattractants that are relevant tousual lymphocyte circulation dynamics. Lymphocytosis with ibrutinib isseen within 1-2 weeks of starting therapy, reaches plateau within thefirst 2-3 cycles, and has resolved over time in virtually all patients.The duration of lymphocytosis does not appear to be related to the depthof eventual response nor to response duration. Woyach, et al., Prolongedlymphocytosis during ibrutinib therapy is associated with distinctmolecular characteristics and does not indicate a suboptimal response totherapy. Blood 2014, 123, 1810-7. Response to ibrutinib occursindependently of high-risk genomic features including IgV_(H) mutationalstatus and del(17p13.1). Responses to this drug have been durable aswell, with an estimated 26 month PFS of 76% and OS of 83% for theserelapsed and refractory patients. This study also included a cohort of31 previously untreated patients. With 16.6 months of follow-up, ORR is71%, with an additional 10% of patients having persistent lymphocytosis;estimated 22 month PFS is 96%. This agent is currently in Phase 3 trialsin treatment-naïve disease and is currently FDA approved for thetreatment of relapsed CLL. These data with ibrutinib support thepotential benefits of selective BTK inhibition in CLL. However, whilehighly potent in inhibiting BTK, ibrutinib has also shown in vitroactivity against other kinases (e.g., epidermal growth factor receptor),which may be the cause of ibrutinib-related diarrhea and rash.Honigberg, et al., The Bruton tyrosine kinase inhibitor PCI-32765 blocksB-cell activation and is efficacious in models of autoimmune disease andB-cell malignancy. Proc. Natl. Acad. Sci. USA 2010, 107, 13075-13080. Inaddition, it is a substrate for both cytochrome P450 (CYP) enzymes3A4/5, which increases the possibility of drug-drug interactions.Finally, the inhibition of ITK that is seen with ibrutinib has thepotential to abrogate NK cell ADCC, which makes combination withmonoclonal antibodies less effective. Kohrt, et al., Ibrutinibantagonizes rituximab-dependent NK cell-mediated cytotoxicity. Blood2014, 123, 1957-60. These liabilities support the development ofalternative BTK inhibitors for use in the therapy of lymphoid cancers.

In this Phase 1B study, two cohorts (relapsed/refractory andtreatment-naïve) will be evaluated with slightly staggered enrollment.First, 6 subjects with R/R CLL will be enrolled into Cohort 1. Once thesafety has been evaluated, the R/R cohort will be expanded to 26subjects and enrollment of 6 treatment-naïve subjects can begin inCohort 2. Once safety is established for Cohort 2, then the cohort willbe expanded to 19 subjects.

Formula (XVIII) will be administered starting cycle 1 day 1 and will beadministered twice daily (100 mg BID) until disease progression.Obinutuzumab will be given in the standard dosing fashion starting oncycle 2 day 1. On cycle 2 day 1, patients will receive 100 mg IV. Oncycle 2 day 2, patients will receive 900 mg. On cycle 2 days 8 and 15,patients will receive 1000 mg IV. On cycles 3-7, patients will receive1000 mg on day 1 of each cycle. For patients treated at dose level −1,100 mg will be given on Day 1 and 650 mg on Day 2 of Cycle 2. On cycle 2day 8 and 15, patients will receive 750 mg IV and during cycles 3-7,patients will receive 750 mg on Day 1 of each cycle. It is acceptablefor cycles to begin <a 24-hour (1 business day) window before and afterthe protocol-defined date for Day 1 of a new cycle.

The inclusion criteria for patient eligibility are as follows: (1)Patients with a diagnosis of intermediate or high risk CLL (or variantimmunophenotype), SLL, or B-PLL by IWCLL 2008 criteria” who have: (a)COHORT 1: Previously received at least one therapy for their disease;(b) COHORT 2: Previously untreated disease and >65 years old OR under 65years old and refuse or are ineligible for chemoimmunotherapy; (2)Patients on Cohort 1 may have received previous ibrutinib (or anotherBTK inhibitor) as long as discontinuation was for a reason other than“on-treatment” disease progression; (3) All patients must satisfy one ofthe following criteria for active disease requiring therapy: (a)Evidence of marrow failure as manifested by the development or worseningof anemia or thrombocytopenia (not attributable to autoimmune hemolyticanemia or thrombocytopenia); (b) Massive (>6 cm below the costalmargin), progressive or symptomatic splenomegaly; (c) Massive nodes (>10cm) or progressive or symptomatic lymphadenopathy; (d) Constitutionalsymptoms, which include any of the following: Unintentional weight lossof 10% or more within 6 months, Significant fatigue limiting activity,Fevers >100.5 degrees F. for 2 weeks or more without evidence ofinfection, Night sweats >1 month without evidence of infection; (4)Measurable nodal disease by computed tomography (CT). Measurable nodaldisease is defined as >1 lymph node >1.5 cm in the longest diameter in asite; (5) Patients with a history of Richter's syndrome are eligible ifthey now have evidence of CLL only, with <10% large cells in the bonemarrow; (6) Subjects must have adequate organ function, defined ascreatinine <2.5 times the upper limit of normal (ULN), ALT and AST<3.0×ULN, and bilirubin <2.5×ULN; (7) Platelets >50×10⁹/L. In subjectswith CLL involvement of the marrow, >30×10⁹/L; (8) ANC >750/mm³ Insubjects with CLL involvement of the marrow, ANC >500/mm³; (9) Subjectmust have an ECOG performance status <2; (10) Subject must not havesecondary cancers that result in a life expectancy of <2 years or thatwould confound assessment of toxicity in this study; (11) Subjects mustbe >18 years of age; (12) Subject must provide written informed consent.A signed copy of the consent form will be retained in the patient'schart; (13) Subject must be able to receive outpatient treatment andfollow-up at the treating institution; (14) Subject must have completedall CLL therapies >4 weeks prior to first study dose. Palliativesteroids are allowed, but must be at a dose equivalent of <20 mgprednisone daily for at least 1 week prior to treatment initiation; (15)Subjects capable of reproduction and male subjects who have partnerscapable of reproduction must agree to use an effective contraceptivemethod during the course of the study and for 2 months following thecompletion of their last treatment. Females of childbearing potentialmust have a negative β-hCG pregnancy test result within 3 days of firststudy dose. Female patients who are surgically sterilized or who are >45years old and have not experienced menses for >2 years may havether3-hCG pregnancy test waived; (16) Subjects must be able to swallowwhole capsules.

The exclusion criteria for patient eligibility are as follows: (1) Forcohort 1, previous therapy for CLL. Treatment of autoimmunecomplications of CLL with steroids or rituximab is allowed, however,CD20 must have returned on 10% of the CLL cells if rituximab wasrecently administered. Palliative steroids are acceptable at doses <20mg prednisone equivalent daily; (2) Any life-threatening illness,medical condition, or organ dysfunction which, in the investigator'sopinion, could compromise the patients' safety, interfere with theabsorption or metabolism of Formula (XVIII), or put the study outcomesat undue risk; (3) Female subjects who are pregnant or breastfeeding;(4) Subjects with active cardiovascular disease not medically controlledor those who have had myocardial infarction in the past 6 months, orQTc >480 ms; (5) Malabsorption syndrome, disease significantly affectinggastrointestinal function, or resection of the stomach or small bowel orgastric bypass, ulcerative colitis, symptomatic inflammatory boweldisease, or partial or complete bowel obstruction; (6) Grade 2 toxicity(other than alopecia) continuing from prior anticancer therapy includingradiation; (7) Major surgery within 4 weeks before first dose of studydrug; (8) History of a bleeding diathesis (e.g., hemophilia, vonWillebrand disease); (9) Uncontrolled autoimmune hemolytic anemia oridiopathic thrombocytopenia purpura; (10) History of stroke orintracranial hemorrhage within 6 months before the first dose of studydrug; (11) Requires or receiving anticoagulation with warfarin orequivalent vitamin K antagonists (eg, phenprocoumon) within 28 days offirst dose of study drug; (12) Requires treatment with long-actingproton pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole,dexlansoprazole, rabeprazole, or pantoprazole); (13) Subjects withactive infections requiring IV antibiotic/antiviral therapy are noteligible for entry onto the study until resolution of the infection.Patients on prophylactic antibiotics or antivirals are acceptable; (14)Subjects with history of or ongoing drug-induced pneumonitis; (15)Subjects with human immunodeficiency virus (HIV) or active infectionwith hepatitis C virus (HCV) or hepatitis B virus (HBV) or anyuncontrolled active systemic infection; (16) Subjects who are known tohave Hepatitis B infection or who are hepatitis B core antibody orsurface antigen positive. Patients receiving prophylactic WIG may havefalse positive hepatitis serologies. Patients who are on WIG who havepositive hepatitis serologies must have a negative hepatitis B DNA to beeligible; (17) Subjects with substance abuse or other medical orpsychiatric conditions that, in the opinion of the investigator, wouldconfound study interpretation or affect the patient's ability totolerate or complete the study; (18) Subjects cannot concurrentlyparticipate in another therapeutic clinical trial; (19) Subjects whohave received a live virus vaccination within 1 month of starting studydrug.

In this study, Formula (XVIII) is administered 100 mg BID, with thesecond dose 11-13 hours after the first. Obinutuzumab is administered byIV infusion as an absolute (flat) dose. Obinutuzumab is administered ina single day, with the exception of the first administration whenpatients receive their first dose of obinutuzumab over two consecutivedays (split dose) in Cycle 2: 100 mg on Day 1 and 900 mg on Day 2. Forpatients treated at dose level −1 (750 mg obinutuzumab), −100 mg will begiven on Day 1 and 650 mg on Day 2. On days when both Formula (XVIII)and obinutuzumab are given, the order of study treatment administrationwill be Formula (XVIII) followed at least 1 hour later by obinutuzumab.The full dosing schedule is given in Table 13.

TABLE 13 Dosing of obinutuzumab during 6 treatment cycles each of 28days duration. Rate of Infusion (In the absence of infusion Day of Doseof reactions/hypersensitivity during Treatment Cycle Obinutuzumabprevious infusions) Cycle 2 Day 1  100 mg Administer at 25 mg/hr over(loading 4 hours. Do not increase the doses) infusion rate. Day 2  900mg Administer at 50 mg/hr. The rate of the infusion can be escalated inincrements of 50 mg/hr every 30 minutes to a maximum rate of 400 mg/hr.Day 8 1000 mg Infusions can be started at a rate of Day 15 1000 mg 100mg/hr and increased by Cycles 3-7 Day 1 1000 mg 100 mg/hr incrementsevery 30 minutes to a maximum of 400 mg/hr.

Anti-CD20 antibodies have a known safety profile, which include infusionrelated reactions (IRR). Anti-CD20 antibodies, and in particularobinutuzumab, can cause severe and life threatening infusion reactions.Sequelae of the infusion reactions include patient discontinuations fromantibody treatment leading to suboptimal efficacy or increased medicalresource utilization, such as hospitalization for hypotension orprolonged antibody infusion time. In the initial study of obinutuzumabin relapsed/refractory CLL patients (Cartron, et al., Blood 2014, 124,2196), all patients (n=13) in the Phase 1 portion experienced IRRs (15%Grade 3, no Grade 4, and 100% patients experienced all grade AE), withhypotension and pyrexia the most common symptoms. In the Phase 2 portionof the study, 95% of patients developed IRR, with 60% of casesdeveloping symptoms of hypotension; of those, 25% were Grade 3reactions. In the pivotal trial of obinutuzumab and chlorambucil inpreviously untreated patients, 69% developed infusion related reactions,of which 21% were grade 3-4.

The results of the Phase 1b study described in this example for Formula(XVIII) in combination with obinutuzumab for patients withrelapsed/refractory or untreated CLL/SLL/PLL are as follows. 6 patientshave been treated in the study to date with the combination of Formula(XVIII) and obinutuzumab. Patients are first treated with a month run-inof Formula (XVIII) alone, then on cycle 2, day 1, patients are givenobinutuzumab. To date, 41 doses of obinutuzumab have been administeredto 6 patients. Lymphocyte counts immediately prior to treatment withobinutuzumab have ranged from 8 to 213×10⁹/L. No cases of serious orGrade 3-4 IRR's have been reported. Only 2 patients have hadobinutuzumab temporarily held for chills and arthralgias/sluured,respectively, and were able to complete the planned infusion. Anadditional 3 patients had adverse events within 24 hours of theinfusion, all grade 1 (terms: flushing, palpitations in one patient,rash, and restlessness and headache). Consequently, there has been asubstantial decrease in serious or Grade 3-4 IRR″s with the one monthlead-in of Formula (XVIII), which could potentially lead to higherefficacy for the combination as well as better tolerability, leading toa decrease in medical resource utilization.

Example 12—BTK Inhibitory Effects on MDSCs in the Solid TumorMicroenvironment

A molecular probe assay was used to calculate the percent irreversibleoccupancy of total BTK. MDSCs were purified from tumor bearing PDA mice(as described previously) dosed at 15 mg/kg BID of Formula (XVIII).Complete BTK occupancy is observed for both the granulocytic andmonocytic MDSC compartment on Day 8 at 4 hours post dose (N=5). Theresults are shown in FIG. 124.

We claim:
 1. A method of treating a hyperproliferative disease,comprising co-administering, to a mammal in need thereof,therapeutically effective amounts of (1) a Janus kinase-2 (JAK-2)inhibitor, and (2) a Bruton's tyrosine kinase (BTK) inhibitor.
 2. Themethod of claim 1, wherein the BTK inhibitor is selected from the groupconsisting of:


3. The method of claim 1, wherein the BTK inhibitor is selected from thegroup consisting of:


4. The method of claim 1, wherein the JAK-2 inhibitor is selected fromthe group consisting of:


5. The method of claim 1, further comprising the step of administering atherapeutically effective amount of an anti-CD20 antibody selected fromthe group consisting of rituximab, obinutuzumab, ofatumumab, veltuzumab,tositumomab, and ibritumomab.
 6. The method of claim 1, furthercomprising the step of administering a phosphoinositide 3-kinase (PI3K)inhibitor.
 7. The method of claim 6, wherein the PI3K inhibitor is aPI3K-δ inhibitor.
 8. The method of claim 6, wherein the PI3K inhibitoris selected from the group consisting of:


9. The method of claim 1, wherein the hyperproliferative disease is acancer, and the cancer is a B cell hematological malignancy, and whereinthe B cell hematological malignancy is selected from the groupconsisting of chronic lymphocytic leukemia (CLL), small lymphocyticleukemia (SLL), non-Hodgkin's lymphoma (NHL), diffuse large B celllymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL),Hodgkin's lymphoma, B cell acute lymphoblastic leukemia (B-ALL),Burkitt's lymphoma, Waldenström's macroglobulinemia (WM), Burkitt'slymphoma, multiple myeloma, and myelofibrosis.
 10. The method of claim1, wherein the hyperproliferative disease is a cancer, and wherein thecancer is a solid tumor cancer, and wherein the solid tumor cancer isselected from the group consisting of bladder cancer, non-small celllung cancer, cervical cancer, anal cancer, pancreatic cancer, squamouscell carcinoma including head and neck cancer, renal cell carcinoma,melanoma, ovarian cancer, small cell lung cancer, glioblastoma,gastrointestinal stromal tumor, breast cancer, lung cancer, colorectalcancer, thyroid cancer, bone sarcoma, stomach cancer, oral cavitycancer, oropharyngeal cancer, gastric cancer, kidney cancer, livercancer, prostate cancer, esophageal cancer, testicular cancer,gynecological cancer, colon cancer, and brain cancer.
 11. A method oftreating a cancer in a human comprising the step of co-administering (1)a therapeutically effective amount of a Janus kinase-2 (JAK-2)inhibitor, and (2) a therapeutically effective amount of a Bruton'styrosine kinase (BTK) inhibitor, wherein the therapeutically effectiveamount is effective to inhibit signaling between a tumor cell of thecancer and at least one tumor microenvironment selected from the groupconsisting of macrophages, monocytes, mast cells, helper T cells,cytotoxic T cells, regulatory T cells, natural killer cells,myeloid-derived suppressor cells, regulatory B cells, neutrophils,dendritic cells, and fibroblasts.
 12. The method of claim 11, whereinthe cancer is a solid tumor cancer selected from the group consisting ofbladder cancer, non-small cell lung cancer, cervical cancer, analcancer, pancreatic cancer, squamous cell carcinoma including head andneck cancer, renal cell carcinoma, melanoma, ovarian cancer, small celllung cancer, glioblastoma, gastrointestinal stromal tumor, breastcancer, lung cancer, colorectal cancer, thyroid cancer, bone sarcoma,stomach cancer, oral cavity cancer, oropharyngeal cancer, gastriccancer, kidney cancer, liver cancer, prostate cancer, esophageal cancer,testicular cancer, gynecological cancer, colon cancer, and brain cancer.13. The method of claim 11, wherein the BTK inhibitor is selected fromthe group consisting of:


14. The method of claim 11, wherein the JAK-2 inhibitor is selected fromthe group consisting of:


15. The method of claim 11, further comprising the step of administeringa therapeutically effective amount of a phosphoinositide 3-kinase (PI3K)inhibitor.
 16. The method of claim 15, wherein the PI3K inhibitor isselected from the group consisting of:


17. A pharmaceutical composition comprising (1) a Janus kinase-2 (JAK-2)inhibitor; and (2) a Bruton's tyrosine kinase (BTK) inhibitor present inan amount therapeutically effective to treat a hyperproliferativedisease.
 18. The composition of claim 17, wherein the BTK inhibitor isselected from the group consisting of:


19. The composition of claim 17, wherein the BTK inhibitor is selectedfrom the group consisting of:


20. The composition of claim 17, wherein the JAK-2 inhibitor is selectedfrom the group consisting of:


21. The composition of claim 17, further comprising a therapeuticallyeffective amount of an anti-CD20 antibody selected from the groupconsisting of rituximab, obinutuzumab, ofatumumab, veltuzumab,tositumomab, and ibritumomab.
 22. The composition of claim 17, furthercomprising a phosphoinositide 3-kinase (PI3K) inhibitor.
 23. Thecomposition of claim 22, wherein the PI3K inhibitor is a PI3K-δinhibitor.
 24. The composition of claim 23, wherein the PI3K-δ inhibitoris selected from the group consisting of:


25. The composition of claim 17, wherein the hyperproliferative diseaseis a cancer, and the cancer is a B cell hematological malignancy, andwherein the B cell hematological malignancy is selected from the groupconsisting of chronic lymphocytic leukemia (CLL), small lymphocyticleukemia (SLL), non-Hodgkin's lymphoma (NHL), diffuse large B celllymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL),Hodgkin's lymphoma, B cell acute lymphoblastic leukemia (B-ALL),Burkitt's lymphoma, Waldenström's macroglobulinemia (WM), Burkitt'slymphoma, multiple myeloma, and myelofibrosis.
 26. The composition ofclaim 17, wherein the hyperproliferative disease is a cancer, andwherein the cancer is a solid tumor cancer, and wherein the solid tumorcancer is selected from the group consisting of bladder cancer,non-small cell lung cancer, cervical cancer, anal cancer, pancreaticcancer, squamous cell carcinoma including head and neck cancer, renalcell carcinoma, melanoma, ovarian cancer, small cell lung cancer,glioblastoma, gastrointestinal stromal tumor, breast cancer, lungcancer, colorectal cancer, thyroid cancer, bone sarcoma, stomach cancer,oral cavity cancer, oropharyngeal cancer, gastric cancer, kidney cancer,liver cancer, prostate cancer, esophageal cancer, testicular cancer,gynecological cancer, colon cancer, and brain cancer.